1

Introduction to the Pigmentary System

1.1 Introduction

The colors of mice, horses, dogs, rabbits, humans, and other animals – yellow, black, brown, cream,orange, chocolate, blue, beige, white – result from mutations in genes that influence some of themost basic genetically controlled processes of life. These include specification of cell lineage, migra-tion and homing of specialized cells, tissues, and organs, interactions of cells with surrounding tissues and their differentiation, and maintenance throughout life. Because defects in pigment cellsare usually not lethal to the organism, pigmentation is an unusually accessible system in which tostudy these basic processes of vertebrate life.

In addition to these useful qualities of the pigmentary system, the availability of inbred mice withgenetic defects in pigmentation that can be studied using modern techniques of genetics and cellbiology – and comparative genetics at the level of sequenced genomes – has resulted in an unprece-dented explosion of information about pigmentation.

The pigmentary system of the inbred laboratory mouse is a uniquely useful model of phenotype-based genetics, both basic and applied (Lauber 1971; Morse 1978; Barsh 2007). With theinbred mouse, the sequenced genome, modern technologies, and the pigmentary model we havethe necessary tools to unravel the complex web of interacting genic functions that lead from achange in a gene through the multiple communicating processes that result in a specific phenotypicoutcome.

Study of pigmentary genetics began, at the turn of the last century, with yellow mice and albinomice (Cuénot 1902; Castle & Allen 1903; Little 1913a; Wright 1917). A few books serve as landmarksof the progress of our studies of the genetic control over murine and comparative phenotypes;prominent among them are Green’s (1966) Biology of the Laboratory Mouse, Searle’s (1968)Comparative Coat Color Genetics in Mammals, Silvers’ (1979) The Coat Colors of Mice, and Nordlund et al.’s (2006) The Pigmentary System. See also Foster (1965). More recent technological advances havegiven us the tools to take a closer look at the interacting processes that generate specific pigmentaryphenotypes of the mouse, our most valuable genetically controlled animal model (Fig. 1.2).

The Colors of Mice: A Model Genetic Network, 1st edition. By M. Lynn Lamoreux, Véronique Delmas, Lionel Larue, andDorothy C. Bennett. Published 2010 by Blackwell Publishing Ltd.

9781405179546_4_001 2/23/10 2:04 PM Page 3

COPYRIG

HTED M

ATERIAL

4 PART I INTRODUCTION TO THE PIGMENTARY SYSTEM

1.2 Colors of vertebrate animals

The function of melanocytes is to deposit melanin pigment within their cell-specific organelles(melanosomes). In the skin and/or growing hairs (feathers, scales) these melanosomes are oftendelivered to neighboring keratinocytes. Pigment cells of the eye arise in situ and retain theirmelanosomes; pigment cells of other organs may also retain their melanosomes. The colors of thenative pigment – but not all the phenotypes of mice and other mammals – are red/yellow pheome-lanin and black or brown eumelanin. Yellow, black, and chocolate brown are the three basic colorsof pigment produced in mammalian melanocytes (see Chapter 4 on melanogenesis and Chapter 5on pigment-type switching). Additionally, some colors are affected by the blood in the tissues, as forexample in the comb and wattles of chickens, and other colors are influenced primarily by the struc-tures of skin and hair (Quevedo & Holstein 2006), but most color variables, especially in animalsthat are covered with hair or feathers, are created by genetically controlled modification of theamount and distribution of the three basic colors of melanin pigment and of the melanocytes themselves (Searle 1968; Silvers 1979).

Pheomelanin is yellow/red melanin pigment found, for example in the hairs of Golden Retrieverand Irish Setter breeds of dogs; yellow mice, rabbits and guinea pigs, orange or red cats, sorrel orchestnut horses, ‘red’ chickens (Fig. 1.3), ‘brown’ cattle (Fig. 1.4), and the bright red hair of humans(Little 1957; Searle 1968; Robinson 1971; Bowling & Ruvinsky 2000; Ostrander et al. 2005; Pontiuset al. 2007; Schmutz & Berryere 2007; Barsh 2007; see Chapter 5). Eumelanic pigment is of two varieties: black eumelanin, as in the hairs of black Labrador Retriever dogs, and brown eumelanin,as in brown (chocolate) Labrador Retrievers, as well as chestnut Oriental Shorthair cats (see the pic-ture under Statement regarding the use of pictures at the front of the book), brown mice (Fig. 1.5),and others.

Some of the phenotypes that we think of as ‘brown’ actually are not brown at the level of pigmentcolor, and this is also true of ‘red’ or ‘yellow.’ It’s not always easy to tell the difference visually, and

Figure 1.2 White spotted mouse, red-eyed-white, genotype Mitf rw/Mitf rw.

9781405179546_4_001 2/23/10 2:04 PM Page 4

CHAPTER 1 INTRODUCTION TO THE PIGMENTARY SYSTEM 5

Figure 1.3 Pheomelanic chicken, genotype unknown.

Figure 1.4 Pheomelanic calf/cow, Mc1r e/Mc1r e (original name e /e); genotype nameRecessive yellow. The common name is ‘red’ or ‘brown’; however, brown is technicallyincorrect as Brown is an allele of the black /brown Tyrp1 locus (Chapter 4).

9781405179546_4_001 2/23/10 2:04 PM Page 5

6 PART I INTRODUCTION TO THE PIGMENTARY SYSTEM

the common names for color phenotypes are not based on science. Sometimes the word brown isused to describe animals that are pheomelanic, like the cow and calf in Figure 1.4, that may be calledbrown or red; sometimes the word brown is used instead of the more accurate term agouti for phenotypes such as the mouse in Figure 1.6 and the cat in Figure 1.7. Agouti coloration – such as

Figure 1.5 Eumelanic mice, one brown, one black; Tyrp1b/Tyrp1b (former name b /b),phenotype brown; Tyrp1B/Tyrp1B (formerly B /B ), phenotype black.

Figure 1.6 Agouti black mouse and nonagouti black mouse; A /A Tyrp1B/Tyrp1B (formername A /A B /B); a /a Tyrp1B/Tyrp1B (former name a /a B /B ). The hairs of the agouti mouseare banded with yellow pigment and nonyellow pigment as determined by the Agouti locus.The color of the nonyellow pigment is black, as determined at the black /brown (Tyrp1) locus.

9781405179546_4_001 2/23/10 2:04 PM Page 6

CHAPTER 1 INTRODUCTION TO THE PIGMENTARY SYSTEM 7

the wild type in the mouse, rabbit, cat, guinea pig, and squirrel (Fig. 2.5), actually most mammals –consists of patterns (bands) of eumelanin and pheomelanin within individual hairs. These are produced by pigment-type switching, with switching between the deposition of eumelanic andpheomelanic pigment, into the growing hair at different times in its creation, as discussed in Chapter 5. We will reserve the word ‘brown’ for phenotypes that are based on brown eumelanin.

Mammals may produce eumelanin or pheomelanin in the same or different melanocytes. Thischoice is under direct genetic control. In mice, pheomelanin may be produced in the skin of tail andears; otherwise pheomelanin is not normally produced outside the hair follicles. Other mammals,however, do produce pheomelanin in the skin; for example, humans, rabbits, and guinea pigs.

Color of pigment is not the only cause of variability in phenotypes. Banding patterns of hairs havealready been described. Pheomelanin and eumelanin may also be distributed in specific patternsover the body surface. Normal black (or brown) and yellow color patterns such as those of tigers and ocelots, black (or brown)-and-tan patterns of mice or dogs (Fig. 1.8), brindle dogs (Fig. 1.9) and cows (Fig. 5.11), and tabby cats, as well as the agouti pattern of hair banding (Fig. 5.8),are exquisitely controlled and are caused by pigment-type switching as discussed in Chapter 5.

Figure 1.7 An Agouti (A /A) cat of the Abyssinian breed. The name of a breed of animaldoes not relate to the genetics of its pigmentation.

9781405179546_4_001 2/23/10 2:04 PM Page 7

8 PART I INTRODUCTION TO THE PIGMENTARY SYSTEM

Figure 1.8 Black-and-tan dog with white spotting; at/at Tyrp1B/Tyrp1B (former name at/at,B /B ). The specific white-spotting genotype is unknown, but it does not relate to the Agoutigene locus or the Tyrp1 locus. This is another example of the patterning function of theAgouti locus. The Agouti locus regulates patterns of yellow pheomelanin and nonyelloweumelanin on individual hairs, as in Figures 1.6 and 1.7, or patterns of pheomelanin andeumelanin over the surface of the body. The so-called tan portion of the pattern is actuallypheomelanic (yellow) pigment. The black color of the eumelanic portion is determined bythe Black /brown locus (Kerns et al. 2004).

Pigment-type switching describes the ability of pigment cells to switch between the productionof eumelanin and pheomelanin, under the control of the Agouti (A) and/or Extension (Mc1r) loci andmodifying genes. The Agouti locus regulates the pattern of distribution of eumelanin and pheome-lanin on each hair and over the surface of the body. So, agouti is not so much a color as a pattern ofpheomelanogenesis that may or may not occur. That the pigment switch is between eumelanin andpheomelanin is illustrated, for example, in the Doberman Pinscher dog (or the similarly pigmenteddog in Fig. 1.8). These may display yellow and black pigment patterns, or yellow and brown pat-terns in chocolate brown (incorrectly named ‘red’) Doberman Pinscher dogs.

Black and brown combinations do not occur. The type of eumelanin pigment, black versusbrown, is genetically determined at birth, by the genotype at the B (Tyrp1, black/brown) locus, andthere is no mechanism for switching between them. Color switching is exclusively a phenomenoninvolving eumelanin and pheomelanin.

In the mouse and other mammals, the three basic colors of melanin pigment, and their patternsof distribution over the body or within individual hairs, are regulated by the Agouti (A), Extension(Recessive yellow, E, or Mc1r), and black/brown (B or Tyrp1) loci (see Chapter 4).

Two basic types of pigment pattern exist that involve the death of melanocytes or their failure todifferentiate or survive. White spotting is defined as the congenital absence of pigment cells fromportions of the body or from the entire body, and we will use the term progressive graying to

9781405179546_4_001 2/23/10 2:04 PM Page 8

CHAPTER 1 INTRODUCTION TO THE PIGMENTARY SYSTEM 9

describe ongoing loss of melanocytes in mice. Everyone has seen progressive graying with age,caused by loss or death of pigment cells from the hair follicles. Premature graying or patternedgraying may be termed vitiligo or hypopigmentation; these are discussed in Chapter 3 (see also Fig. 1.10). Here we will use vitiligo and avoid the term hypopigmentation because it is not specificto an etiology.

Examples of white spotting include Paint horses, Hereford cattle, white forelock in humans, andthe white areas of white-spotted cats, dogs, and mice, many of which are pictured throughout thisbook, especially in Chapter 3. The terms partial albinism and hypopigmentation are sometimessubstituted for white spotting, especially in older publications. However, these are not appropriateto specifically describe white spotting, because hypopigmentation is a term also applied to albinism,which is a fundamentally different process. White-spotting and progressive-graying phenotypesresult from pigment cell death or failure to survive, whereas albinism is the failure of deposition ofpigment in living pigment cells, as discussed in Chapter 4.

The final step in cutaneous pigmentation occurs when the pigment cell transfers itsmelanosomes into keratinocytes of the adjacent skin, or the keratinocytes of a growing hair orfeather as discussed in Chapter 4. The distribution of melanosomes in hairs is precise, and is an

Figure 1.9 Franny and Bitsy, a white-spotted dog of the Border Collie breed and brindle-colored Catahoula Hound. Both dogs have white spotting of unknown genotype that is notassociated with the other color genotypes. Both dogs are Black at the Black /brown locus;therefore, eumelanic areas are black. The brindle phenotype is associated with mutation ata third locus that regulates the eumelanin/pheomelanin alternative in dogs (the K, Canineb -defensin 103 locus).

9781405179546_4_001 2/23/10 2:04 PM Page 9

10 PART I INTRODUCTION TO THE PIGMENTARY SYSTEM

important component of how we perceive the color. When this pattern of distribution is modifiedby mutation, if the change causes the fur coat or feathers to reflect light differently to our eyes, theanimal may appear to be quite a different color. In mammals, the most common example of thistype of genetically controlled color difference is found in the ‘dilute’ phenotypes that are variouslyreferred to as gray or blue, lavender, or cream (there are yet more names for this phenotype in various species) colors of cats, dogs, and other mammals (see Fig. 1.11). These may be caused bymutation at several different loci. We discuss melanosomal transfer briefly below in section 1.8 andin more detail in Chapter 4.

Figure 1.10 Vitiligo; (a) Mitf vit/Mitf mi-rw; (b) Mitf mi-vit/Mitf mi-or. The Vitiligo mouse has bothwhite spotting and vitiligo. (a) This mouse is in the process of molting to a lighter color. (b) The older mouse is shown at the rear.

(a)

(b)

9781405179546_4_001 2/23/10 2:04 PM Page 10

CHAPTER 1 INTRODUCTION TO THE PIGMENTARY SYSTEM 11

To summarize, the complexity of pigmentation phenotypes results primarily from four basicprocesses:

1 development of the melanocyte (Chapter 3);2 differentiation of the melanocyte as it generates melanosomes (Chapter 4);3 regulation of the type of melanin that is deposited upon the melanosome (pheomelanin, black

eumelanin, or brown eumelanin) (Chapter 5);4 transport of the melanosome within the pigment cell and transfer to the neighboring

keratinocytes (Chapter 4).

These four basic functions are regulated by over 300 gene loci in the laboratory mouse (see the Appendix to this chapter). In the mouse, any of these genes can be evaluated using natural or

Figure 1.11 Mini Mizzle, lavender color, oriental shorthair. Oriental shorthair is the nameof a breed of cat, and is therefore not a color. ‘Lavender’ is a cat fancier’s term for‘nonagouti, brown, dilute’ Unfortunately, ‘dilute’ is the cat breeder’s term for the mousegene known as Leaden (Melanophilin). The mouse Dilute gene identifies the Myo5a locus.The genotype of this cat is a /a Tyrp1b/Tyrp1b MlphIn/MlphIn, which cat fanciers would referto as a /a b /b d /d; however, the correct original nomenclature is a /a b /b In /In.

9781405179546_4_001 2/23/10 2:04 PM Page 11

12 PART I INTRODUCTION TO THE PIGMENTARY SYSTEM

created mutations against an inbred background genome and using advanced genetic techniques(see Chapter 6). The mutant mice, or their cells, are usually viable and can be evaluated at everylevel of gene function, from transcription to the final mouse phenotype. This makes the pigmentsystem of mice uniquely valuable to our understanding of basic biological processes, including celland tissue communication networks within the developing embryo and the adult body, and specificmedical conditions, including melanoma.

1.3 Other pigment cells

Chromatophores or chromatocytes (colored cells) are general terms for pigment cells, which insome vertebrates may produce pigments other than melanin. Chromatophores of vertebrates –fish, amphibians, reptiles, birds, and mammals – provide protection from the environment as wellas adaptive and/or disruptive coloration, through the colors of their pigments and the movement oftheir pigmented organelles (chromatosomes) within the pigment cells (Bagnara & Matsumoto2006; Logan et al. 2006). The chromatophores of fishes, amphibians, and some reptiles are morevaried in content and function than those of birds and mammals, and generally retain their pigmentrather than transferring it to other cells. Colors of lower vertebrates thus result from the distribu-tion of dermal and epidermal pigment cells (Lamoreux et al. 2005; Parichy et al. 2006). Fish chro-matophores are primarily melanophores/melanocytes that produce black or brown melaninpigment; leucophores (white) and iridophores (shiny silvery colors), both of which use purines tocreate their pigments; and the yellow-red xanthophores. The yellow colors of fish xanthophores,unlike the pheomelanocytes of birds and mammals, are based in pteridine pigments (Ziegler 2003).Color changes in the dermal melanophores of fishes, amphibians, and reptiles may be rapid and varied, because the pigment cells can quickly disperse or aggregate their chromatosomes withinthe dermal chromatophores in response to neuronal and hormonal controls.

The pigmentation repertoire of mammals and birds is more limited. Mammals and birds do nothave so many types of chromatophores; for the most part, they are limited to epidermalmelanophores. Furthermore, rapid changes in the hair/feather pigmentation pattern of birds andmammals are not possible, except through behaviors such as the tail flagging of deer or courtshipdisplays of birds. There are two reasons for this. First, the hairs of mammals (and feathers of birds)are not living tissue and so cannot change biologically. Secondly, the epidermal melanocytes ofmammals do not normally translocate their melanosomes in response to direct neuronal and hormonal cues, as do the dermal melanophores of amphibians and fishes. Their primary function isto transfer melanosomes into neighboring keratinocytes. They accomplish this function slowly,responding to the environment via the epidermal melanin unit (Klaus 2006; Quevedo & Holstein2006).

1.4 The epidermal melanin unit

The epidermal melanin unit (also called the EMU) of human skin (Fitzpatrick & Breathnach 1963;Quevedo & Holstein 2006) is a subunit of epidermal tissue, in humans consisting of a melanocyteand its 30–40 associated keratinocytes, that together are responsible for the production ofmelanosomes, and their subsequent transport, metabolism, and degradation. As they mature, themelanosomes, which are members of the lysosomal family of organelles, are transferred to adjacentkeratinocytes of a growing hair or, in pigmented skin of humans and some other mammals, to

9781405179546_4_001 2/23/10 2:04 PM Page 12

CHAPTER 1 INTRODUCTION TO THE PIGMENTARY SYSTEM 13

the adjacent keratinocytes of the epidermal melanin unit in the basal layer of the epidermis, where they are sequestered within lysosomes. Because the epidermis grows continually from thebasal layer, the cells of the epidermal melanin unit are pushed upward, gradually cornified as thenormal protective layer of skin, and then lost/shed as new epidermal tissue replaces them frombelow.

In mice, the outermost protective layer is the hair coat. The transfer of melanosomes from thepigment cell into the growing hair is precisely controlled in its distribution within the cortex and themedulla of the hair and differentially according to the type of hair and its location on the body. Inmice, control over the amount, distribution, and color of melanosomes is specific to the age ofmouse, stage of the hair growth cycle, and position on the body (Galbraith 1964).

Mammalian pigment cells are also delivered to the inner ear, iris, choroid, heart, and other extracutaneous locations (Quevedo & Holstein 2006). The retinal pigment epithelium (see Chapter 3)is produced in situ.

1.5 Mammalian hair

In mice, overall pigment phenotype is predominantly a reflection of the hair (fur) that covers thebody. Most of the melanocytes are located in the hair rather than in the interfollicular epidermis.Each hair grows from an epidermal hair follicle (Fig. 1.12). The hair follicle is an ingrowth of the epi-dermis that pushes deep into the dermis and the hypodermis. The hair follicle, where most of theactivity takes place during a hair growth cycle, consists of the hair bulb, the dermal papilla, and thebulge area. The dermal papilla pushes up into the root of the hair bulb and provides a blood supplyto the hair bulb cells, which generate the keratinocytes that become cornified as hair. The bulgearea, at least in mice, sequesters melanocyte stem cells between hair cycles. At the beginning of ahair cycle, melanoblasts (unpigmented melanocyte precursor cells; sometimes called melanocyte

Anagen

Melanocyte

B

Figure 1.12 A mature hair follicle. B indicates the bulge region of the hair follicle and thegray spot shows where the melanocyte stem cells reside. The horizontal line represents thelevel to which the follicle regresses after the growth phase is complete. Diagram courtesy ofNishimura et al. (2002).

9781405179546_4_001 2/23/10 2:04 PM Page 13

14 PART I INTRODUCTION TO THE PIGMENTARY SYSTEM

stem cells in this context) migrate from the bulge area into the hair bulb, around the dermal hairpapilla, where they proliferate, differentiate, and initiate melanogenesis.

1.6 Melanosome biogenesis and translocation

The epidermal melanocyte (Fig. 1.13) is dendritic and contains an abundant endoplasmic reticulumand active Golgi region where melanosomal proteins are processed before being carried to theirspecific locations in stage I, II, III, and the mature stage IV melanosomes, as described in Chapter 4(Fig. 4.8). Correct processing of the melanosomal proteins and their appropriate transport to thedeveloping melanosome are necessary for normal pigmentation. Pigmentary defects associatedwith processing and transport are discussed in Chapter 4.

The melanosome is a member of the family of lysosome-related organelles that also includesplatelet dense granules, lamellar bodies of type II alveolar epithelial cells, and lytic granules of cyto-toxic T lymphocytes and natural killer cells. Premelanosomes appear to derive as ‘saccules’ that budfrom the smooth endoplasmic reticulum (Orlow 1995). In eumelanosomes an internal matrix con-denses from amorphous filamentous material to an organized internal structure. This material islargely the protein product of the Silver gene locus, as discussed in Chapter 4 (Boissy et al. 2006).

When assembled into a stage II melanosome (lacking pigment) the structure appears in sectionas highly organized spirals that apparently represent three-dimensional sheets that are rolled or

Figure 1.13 A eumelanocyte in cell culture.

9781405179546_4_001 2/23/10 2:04 PM Page 14

CHAPTER 1 INTRODUCTION TO THE PIGMENTARY SYSTEM 15

pleated to form the basic structure upon which pigment is deposited in later stage melanosomes(Fig. 4.8). As the melanosome matures beyond stage II to stage III, catalytic enzymes are deliveredto it and initiate deposition of melanin upon and within the matrix of the melanosome until it finallymatures as the fully pigmented, chemically inert stage IV melanosome. In the living cell, the cata-lytic enzymes are active only briefly in the controlled environment of the melanosome, when theyare needed for pigment deposition. During other stages of the cycle, their locations and functionsare controlled tightly by other molecules in the pigment cell, as discussed in Chapter 4. Stage IVmelanosomes are transported to the periphery of the melanocyte and transferred to keratinocytesas discussed in Chapter 4 (Scott 2007; Byers 2006).

1.7 Melanin

Melanogenesis occurs within the melanosome. Failure of melanogenesis results in albinism. Thesubstrate molecule required for initiation of melanogenesis, tyrosine, is found in all cells; it is not alimiting factor. The enzyme tyrosinase is normally the rate-limiting factor, and is sufficient to cata-lyze melanogenesis in vitro. The biochemical pathway is relatively simple, as shown in Figure 1.14.To prevent premature activity of tyrosinase in vivo, the cell maintains tight control over its process-ing and routing to the melanosome, as described in Chapter 4. Genetic defects in tyrosinase itself,encoded at the Albino or Color (Tyr, c) locus, constitute one class of albinism. Other causes ofalbinism most often relate to the loci involved with processing and routing. As mentioned, mam-mals are able to produce two chemically distinct types of melanin pigment: (1) black or browneumelanin and (2) pheomelanin in shades ranging from yellow to red (Chapter 4; Brilliant 2006;Hearing 2006; Oetting & Setaluri 2006; Solano & García-Borrón 2006; Figure 1.15).

Pheomelanosomes differ from eumelanosomes in structure, as well as color and the chemicalnature of the pigment (Ito & Wakamatsu 2006; Sarna & Swartz 2006). These differences result atleast in part from the switching off of several of the gene loci that are responsible for the productionof eumelanosomes, as discussed in Chapter 5, pigment-type switching (and see Barsh 2006), andprobably also in the availability of cysteine substrate.

1.8 Hair growth

As melanosomes mature, they are carried to the outer perimeter of the pigment cell and normallyare transferred into neighboring keratinocytes of the growing hair or feathers in mammals(described in Chapter 4) or birds, and within the skin of humans. In the hair follicle, melanogenesisoccurs during the growth of a new hair. During anagen, the first stage of hair follicle development,which lasts about 17 days in mice, the hair follicle extends deeper into and below the dermis, whilemelanocytes in the bulb area of the follicle (Figure 1.12) transfer melanosomes into the growinghair. Catagen, which lasts about a day, is a transitional second stage of the cycle, after the hair is fullygrown, when a basal club is formed that anchors the hair in the upper part of the hair follicle.Telogen is the resting stage between cycles of hair growth. The length of telogen varies between amonth and several months, depending upon the age of the mouse and other factors such as genet-ics, nutrition, or damage to the hair.

During the anagen or growth stage of the hair follicle, keratinocytes flow upward in the hair shaftfrom the lower hair bulb where they are generated, while melanocytes in the upper hair bulb synthesize melanosomes and deposit them from their long dendritic processes into the living

9781405179546_4_001 2/23/10 2:04 PM Page 15

16 PART I INTRODUCTION TO THE PIGMENTARY SYSTEM

Dopaquinone

Cyclodopa

Dopa

Dopachrome

DHI

EUMELANINPHEOMELANIN

Benzothiazeneintermediates

Cysteinyldopa

+Cysteine–Cysteine

Tyrosinase DHICA oxidase

Dopachrometautomerase (DCT)

Tyrosine

DHICA

Tyrosinase

(b) (c)

(a)

Figure 1.14 (a) The melanogenic pathway functions in the pigment granule (pathwaysimplified from Ito & Wakamatsu 2008; reproduced with permission of Wiley-Blackwell).Enzymes are shown in boxes. The rate-limiting enzyme is tyrosinase; mutation at the Tyr(Albino) locus reduces the amount of melanin that the pigment cell can make. In nonagoutimice that are otherwise wild type at pigment loci, mutation of the gene that encodesdopachrome tautomerase (DCT) results in slaty mice (below left, the one on the lower rightis Slaty, that is, mutant at Dct ). Mutation of the gene with 5,6-dihydroxyindole-2-carboxylicacid (DHICA) oxidase activity (Tyrp1) results in brown mice (b, rear) (see also Chapter 4).The mouse on the left in this picture is wild type. Pheomelanogenesis is primarily regulatedby a cell-surface receptor (MC1R) and its ligand, melanocyte-stimulating hormone (MSH),that control whether or not the cell will make yellow pigment. Pheomelanogenesis isepistatic to eumelanogenesis. The two pheomelanic mice (c) are (front) Recessive yellow,in which the MC1R is mutant, and (back) Lethal yellow, in which the Agouti locus thatencodes MSH is mutant (see also Chapter 5).

keratinocytes. The hairs become pigmented in an exquisitely reproducible fashion that reflects the genotype of the mouse, type of hair, and its location on the body. The resulting hair consists ofvariations on the theme of medullary segments, within which the melanosomes are arranged in aladder-like formation, surrounded by a cortex in which the melanosomes are more or less evenly

9781405179546_4_001 2/23/10 2:04 PM Page 16

CHAPTER 1 INTRODUCTION TO THE PIGMENTARY SYSTEM 17

distributed (Montagna & Ellis 1958; Searle 1968; Quevedo & Holstein 2006). By the time the hairemerges from the shaft of the hair follicle, the keratinocytes are pigmented, cornified, nonlivingappendages to the skin.

1.9 Hair growth cycles

In mice, new hairs replace the old in more or less predictable cycles of growth. The first hairs beginto grow around the time of birth. After the first coat has grown, hair growth cycles can be inducedartificially by plucking or shaving. Normally, the second cycle of hair growth begins at about 7–9weeks of age. Thereafter, cycles of hair growth occur every few months. It may take about 2 weeksto fully replace the coat of hair. The process begins at the head of the mouse and proceeds caudad asa wave of new growth. During this time a continually changing pattern of pigmentation is usuallymore or less obvious, depending upon how much the newer hairs differ in appearance from the old.

Natural molt patterns may be caused by age-related genetic changes in the new hairs, or simplewear and tear of the old. In some mutant phenotypes or strain backgrounds, it is normal for pigmentation to change with age, sometimes resulting in rather dramatic molt patterns, especiallyat first molt (for example, Lamoreux & Galbraith 1986, and Fig. 5.4). Even if there are no devel-opmental differences, the black or brown hairs can become rusty-looking with age, presumablybecause of the bleaching effect of saliva through grooming, and urine in the cage, so that a mouse inthe middle of a hair cycle may have a pattern of shiny black or brown new hairs that contrast withthe rusty-looking hairs, farther back on the body, that are yet to be shed. Similar patterns can be

Figure 1.15 Pheomelanic cat (known by some as ‘red’ and others as ‘orange’ and evenothers as ‘marmalade’). Notice that the darker markings on this yellow cat arepheomelanic, whereas the darker markings on the agouti cat in Figure 1.7 are eumelanic.

9781405179546_4_001 2/23/10 2:04 PM Page 17

18 PART I INTRODUCTION TO THE PIGMENTARY SYSTEM

created artificially by injection (during the hair growth cycle) of substances that alter pigment phenotype (Chapter 5). The artificially created pattern will be maintained until the subsequent natural molt, when the mouse returns to its genetically determined phenotype. Patterns created byhair growth cycles are secondary to the hair cycle itself. Therefore, strictly speaking, they are notprimarily the result of action of ‘pigmentary genes,’ but are nevertheless important to interpreta-tion of pigmentary genetics for a couple of reasons. First, it is important to recognize the differencebetween phenotypes that are under direct genetic control, and those such as the hair cycle patternsthat may not be directly relevant. Second, the hair cycle pattern of mice illustrates the need to be awareof differences between the physiology of humans and of mice that must be taken into considerationwhen interpreting data. The molt cycle of mice differs significantly from the condition in humans.

1.10 Embryonic development of the pigment cell lineage

Development has no beginning, and we hope it will have no end, technology notwithstanding. Foran individual organism, development begins with the zygote, product of the fusion of a haploidsperm with an egg that carries a haploid set of chromosomes plus the extensive egg cytoplasm thatis rich in nutrients and proteins. These proteins, encoded in the genome of the mother, make pos-sible the maturation of offspring by providing enzymes and cellular biochemical structures that support development, from organizing the zygote to mitotic cell divisions and the early steps of cleavage, with the formation of the primary germ layers.

The pigment cell lineage of melanoblasts that mature into melanocytes arises after these earliestevents, during the transient emergence of the neural crest as described in Chapter 3. The odyssey ofneural-crest-derived pigment cells begins when neural-crest cells delaminate from the dorsolateralportion of the neural tube, in the mouse just before or as the neural tube closes. Melanoblasts(immature pigment cells) migrate, while replicating rapidly, along complex pathways. In mice, asthe hair follicles develop concurrently with pigment-cell migration, the melanoblasts home to thefollicles, leaving the interfollicular areas nearly devoid of pigment cells. Some melanoblasts thenenter the bulge area of the follicle and others differentiate in the bulb region to pigment the growinghair as described above. Melanoblasts also migrate through the head and to the nose, eyes, ears, andeven the heart following equally specific migratory pathways. The retinal pigment epithelium (seeChapter 3) is exceptional because it is not neural-crest-derived, but is induced directly in the neuraltube.

1.11 Pigment cells in culture

Pigment cells of course develop normally in the tissue environment, not in cell culture, and thereare differences between the cell culture requirements and biochemical properties of mouse andhuman melanocytes. Additionally, the mature pigment system of mice differs somewhat from thehuman pigment system in vivo, as do some of its functions and associated functional genetics(Sundberg 1994; Green 1966; Boissy et al. 2006; Montoliu et al. 2009). Therefore, it is wise to fullydefine the genetics of biological materials, human or murine, and to use caution when attributingresults across species or genomic lines. That said, the unparalleled availability of murine pig-mentary tissues and melanocytes that are inbred and genetically controlled provides a powerful tool for dissecting the basic mechanisms of melanogenesis at all levels, from the cell to the organism (Nordlund et al. 2006). Comparative mammalian genetics, especially at the molecular and

9781405179546_4_001 2/23/10 2:04 PM Page 18

CHAPTER 1 INTRODUCTION TO THE PIGMENTARY SYSTEM 19

phenotypic levels, has become highly sophisticated; information from the human and other speciesis informing mouse studies, and vice versa.

1.12 Conclusion

The remarkably choreographed accomplishments that result in development and differentiation ofpigment phenotypes are made possible by an intricate web of tissue interactions and cellular signal-ing pathways that direct the functions of the pigment cells at every level of organization from thegene to the whole organism. Through chemical messages received from the environment and re-cognized by its own information-processing pathways, the pigment cell regulates the genes thatdirect the necessary cellular processes. Because pigment cells are easily observed, and their absenceis not lethal, the pigment phenotypes provide an unparalleled model for the study of cellular com-munications and interacting signaling pathways as they function to bring about observable pheno-types summarized above. With the genomes of several species now sequenced, and others rapidlyjoining the databases, we are in a position to evaluate the pigmentary system using reductionist,phenotypic, and comparative methods in parallel.

Figure 1.16 Two dogs that are mutant at different loci influencing the choice betweeneumelanic and pheomelanic pigmentation (discussed in Chapter 5). The dog to the rear(but leading the pack) is a chimeric mix of eumelanic and pheomelanic pigmentationresulting from mutation at the K (Canine b -defensin 103) locus. In this case the eumelanin/pheomelanin switch is regulated via the keratinocytes. See also Figure 5.13 for a betterview of the pattern. The dog in the foreground is mutant at the Agouti (A ) locus thatregulates the eumelanin/pheomelanin switch over the body and on each hair via thegenotype of the mesoderm. Other loci that influence the switch are listed in the Appendix of this chapter, and in Chapter 5. Photograph courtesy of TheOneCreation.

9781405179546_4_001 2/23/10 2:04 PM Page 19

20 PART I INTRODUCTION TO THE PIGMENTARY SYSTEM

Appendix: color loci of the mouse

Introduction

This appendix lists all of the loci that have been reported to contribute to pigmentation to date. Forfurther information and updates we refer you to:

• the Mouse Genome Informatics (MGI) database maintained by The Jackson Laboratory ( JAX),www.informatics.jax.org/;

• the International Federation of Pigment Cell Societies (IFPCS) Color Genes initiative,www.espcr.org/micemut/, maintained by the European Society for Pigment Cell Research(ESPCR) (Montoliu et al. 2009).

Specific (mostly classical) mutant loci are discussed throughout the book in the context of their con-tribution to phenotype. These sections can be identified in the text because they have headings thatlook like the one shown here (e.g. see Chapter 4), and they are listed below in alphabetical order bylocus name.

Silver (Si, Pmel17, Gp100)MGI lists one spontaneous phenotypic alleleAvailability: JAX, CMMR, MMRRC

In such headings, ‘Availability’ refers to the facilities where various resources (mice, frozenembryos, etc.) are available. We use abbreviations for the facilities, and these are listed below.Besides the main ones ( JAX, HAR, ORNL, MMRRC), quite a few other centers that have prolifer-ated internationally with the availability of modern genetic technology (see Chapter 6). These arelisted in full by the International Mouse Strain Resource (IMSR), sponsored by the MGI:www.findmice.org/fetch?page=imsrStrainRepositories.

CARD Center for Animal Resources and DevelopmentCFG Consortium for Functional GlycomicsCMMR Canadian Mouse Mutant RepositoryEMMA European Mouse Mutant ArchiveHAR Mammalian Genetics Unit, HarwellJAX The Jackson LaboratoryKOMP Repository Knockout Mouse RepositoryMMRRC Mutant Mouse Regional Resource CentersORNL Oak Ridge National LaboratoriesRBRC RIKEN BioResource CenterTAC TaconicTIGM Texas A&M Institute for Genomic Medicine

Following is an index to the specific mutant loci, listed by phenotype-based name, that are discussedin the text of this book.

9781405179546_4_001 2/23/10 2:04 PM Page 20

CHAPTER 1 INTRODUCTION TO THE PIGMENTARY SYSTEM 21

Index of mutant loci discussed in text

Agouti (A, Nonagouti, a) Chapter 5, page 197Albino (C, Tyr, Tyrosinase) Chapter 4, page 146Ashen (Ash, Rab27a, RAS oncogene family member RAB27A) Chapter 4, page 175Beige (Bg, Lyst, Lysosomal trafficking regulator) Chapter 4, page 170Belted (Bt, Adamts20, A disintegrin-like and metallopeptidase Chapter 3, page 122

(reprolysin type) with thrombospondin type 1 motif, 20)Buff (Bf, Vps33a, Vacuolar protein sorting 33a) Chapter 4, page 165Cappuccino (Cno) Chapter 4, page 166Chocolate (Cht, Rab38, RAS oncogene #38) Chapter 4, page 165Cocoa (Coa, Hps3, Hermansky–Pudlak syndrome 3 homolog) Chapter 4, page 168Dilute (D, Myo5a, Myosin Va) Chapter 4, page 175Dilute suppressor (Dsu, Melanoregulin, Mreg) Chapter 4, page 175Dominant black (K, CBD103, Canine B-defensin 103) Chapter 5, page 204Dominant megacolon (Dom, Sox10, SRY-related box 10) Chapter 3, page 93Faded (Fe) Chapter 4, page 162Gpnmb (Glycoprotein transmembrane NMB) Chapter 4, page 146Gunmetal (Gm, Rabggta, Rab geranylgeranyl transferase, A subunit) Chapter 4, page 171Kit (c-Kit, W, Dominant white spotting) Chapter 3, pages 98 and 118Leaden (Ln, Mlph, Melanophilin) Chapter 4, page 175Lethal spotting (Ls, Edn3, Endothelin 3) Chapter 3, page 102Light ear (Le, Hps4, Hermansky–Pudlak syndrome 4 homolog) Chapter 4, page 169London gray (Lgr) Chapter 4, page 162Mahogany (Mg, Atrn, Attractin) Chapter 5, page 203Mahoganoid (Md, Mgrn1, Mahogunin ring finger 1) Chapter 5, page 203Microphthalmia (Mi, Mitf, Microphthalmia-associated transcription factor) Chapter 3, page 94Mocha (Mh, Ap3d, Adaptor-related protein complex 3, delta subunit) Chapter 4, page 163Mottled, Mosaic, Pewter, Atp7a (ATPase, Cu2+-transporting, Chapter 4, page 154

A polypeptide, MNK, Menkes protein)Muted (Mu, Txndc5, Thioredoxin domain containing 5) Chapter 4, page 168Ocular albinism 1 (Oa1, Gpr143, G protein-coupled receptor 143) Chapter 4, page 153Pale ear (Ep, Hps1, Hermansky–Pudlak syndrome 1 homolog) Chapter 4, page169Pallid (Pa, Pallidin, Pldn) Chapter 4, page 168Patch (Ph) Chapter 3, page 118Patchwork (Pwk) Chapter 3, page 126Pearl (Pe, Ap3b1, Adaptor-related protein complex 3, B1 subunit) Chapter 4, page 164Piebald (S, Ednrb, Endothelin receptor type B) Chapter 3, page 102Pink-eyed dilution (P, Oca2, Oculocutaneous albinism type II ) Chapter 4, page 156Pro-opiomelanocortin (POMC ) Chapter 5, page 202Recessive yellow (E, Extension, Mc1r, Melanocortin 1 receptor) Chapter 5, page 194Reduced pigmentation (Rp, Bloc1s3; Biogenesis of lysosome-related Chapter 4, page 168

organelles complex-1, subunit 3; Blos3)Ruby-eye (Ru, Hps6, Hermansky–Pudlak syndrome 6 homolog) Chapter 4, page 169Ruby-eye 2 (Ru-2, Hps5, Hermansky–Pudlak syndrome 5 homolog) Chapter 4, page 169Rump white (Rw; not Rumpwhite) Chapter 3, page 118Sandy (Sdy, Dtnbp1, Dystrobrevin-binding protein 1, Dysbindin, Hps7) Chapter 4, page 168

9781405179546_4_001 2/23/10 2:04 PM Page 21

22 PART I INTRODUCTION TO THE PIGMENTARY SYSTEM

Silver (Si, Pmel17, Gp87) Chapter 4, page 140Slaty (Slt, Dct, Dopachrome tautomerase, formerly Trp2, Chapter 4, page 152

Tyrosinase-related protein 2)Splotch (Sp, Pax3, Paired box gene 3) Chapter 3, page 91Steel (Sl, Kitl, Kit ligand, SLF, Steel factor; MGF, Mast cell growth factor; Chapter 3, page 100

SCF, Stem cell factor)Subtle gray (Sut, Slc7a11) Chapter 5, page 204Tyrp1 (Brown, B, Tyrp1, Tyrosinase-related protein 1) Chapter 4, page 150Underwhite (Uw, Matp, Membrane-associated transporter protein, Chapter 4, page 158

Slc45a2, Solute carrier family 45, member 2)

Cloned and uncloned loci

Table A1.1 shows a summary of the cloned mouse color genes and Table A1.2 gives a summary ofthe uncloned mouse color genes.

9781405179546_4_001 2/23/10 2:04 PM Page 22

Tab

le A

1.1

Sum

mar

y of

the

clon

ed m

ouse

col

or g

enes

Sym

bo

l (o

ld s

ymb

ol)

(A) M

elan

ocy

te d

evel

op

men

t – in

volv

ing

inte

gu

men

t

Nam

e (o

ld n

ame)

Mo

use

chro

mo

som

eM

uta

nt p

hen

oty

pe

Mo

lecu

lar/

bio

log

ical

fun

ctio

ns

Hu

man

sy

mb

ol

Hu

man

syn

dro

me

Hu

man

ch

rom

oso

me

Acd

Ada

m17

Ada

mts

20 (b

t)

Apc

Brc

a1

Doc

k7 (m

,mnl

t)

Ece

1

Edn

3 (ls

)

Edn

rb (s

)

adre

noco

rtic

al d

yspl

asia

a di

sint

egrin

and

met

allo

prot

ease

dom

ain

17

a di

sint

egrin

and

met

allo

prot

ease

dom

ain

(rep

roly

sin

type

) with

thro

mbo

spon

din

type

1

mot

if, 2

0 (b

elte

d)

aden

omat

ous

poly

posi

s

coli,

alle

le tm

2Rak

brea

st c

ance

r 1, a

llele

tm2A

rge

dedi

cato

r of c

ytok

ines

is 7

(mis

ty, m

oonl

ight

)

endo

thel

in c

onve

rtin

g

enzy

me

1, a

llele

tm1R

ehen

doth

elin

3 (l

etha

l

spot

ting)

endo

thel

in re

cept

or ty

pe

B (p

ieba

ld s

potti

ng)

8 12 15 18 11 4 4 2 14

Hyp

erpi

gmen

ted

skin

,

adre

nal h

yper

plas

ia, o

ther

orga

n di

sord

ers

Irre

gula

r pig

men

tatio

n in

hairs

Lum

bar w

hite

bel

t

Pre

nata

l dor

sal d

ark

strip

e

and

head

pat

ch

Abn

orm

al s

kin

pigm

enta

tion

Dis

tal w

hite

spo

tting

,

hypo

pigm

ente

d fu

r, b

ut

mel

anoc

ytes

in v

itro

hype

rpig

men

ted

No

mel

anoc

ytes

in u

vea

nor d

orsa

l ski

n at

birt

h

(per

inat

al le

thal

)

Whi

te s

potti

ng,

meg

acol

on a

nd o

ther

neur

al c

rest

def

ects

Whi

te s

potti

ng,

meg

acol

on a

nd o

ther

neur

al c

rest

def

ects

Tel

omer

e ca

ppin

g; m

ay

affe

ct p

igm

enta

tion

thro

ugh

exce

ss A

CT

H

Pro

teas

e, p

roce

ssin

g

vario

us b

ioac

tive

prot

eins

Met

allo

prot

ease

,

mel

anob

last

mig

ratio

n?

Wnt

pat

hway

med

iato

r;

tran

scrip

tion

fact

or

DN

A re

pair;

tum

or

supp

ress

or

wid

ely

expr

esse

d R

ho-

fam

ily g

uani

ne n

ucle

otid

e

exch

ange

fact

or

End

othe

lin s

ynth

esis

Mel

anob

last

/neu

robl

ast

grow

th a

nd d

iffer

entia

tion

fact

or

ED

N3

rece

ptor

AC

D

AD

AM

17

AD

AM

TS

20

AP

C

BR

CA

1

DO

CK

7

EC

E1

ED

N3

ED

NR

B

N N N Ade

nom

atou

s

poly

posi

s co

li

Bre

ast c

ance

r

N N Hirs

chsp

rung

dis

ease

,

Waa

rden

burg

–

Sha

h sy

ndro

me

Hirs

chsp

rung

dis

ease

,

Waa

rden

burg

–

Sha

h sy

ndro

me

16q2

2.1

2p25

12q1

2

5q22

.2

17q2

1

1p31

.3

1p36

.12

20q1

3

13q2

2

9781405179546_4_001 2/23/10 2:04 PM Page 23

Egf

r (D

sk5

)

En1

Fgf

r2

Fox

n1 (t

w)

Fre

m2

Fzd

4

Gat

a3

Gli3

Gna

q (D

sk1,

Dsk

10)

epid

erm

al g

row

th fa

ctor

rece

ptor

(dar

k sk

in 5

)

engr

aile

d 1

fibro

blas

t gro

wth

fact

or

rece

ptor

2

fork

head

box

N1,

alle

le

tw (t

rave

ling

wav

e)

Fra

s1 re

late

d

extr

acel

lula

r mat

rix

prot

ein

2, a

llele

my-

F11

friz

zled

hom

olog

4

(Dro

soph

ila),

alle

le

tm1N

atG

AT

A b

indi

ng p

rote

in 3

,

alle

le tm

3Gsv

GLI

-Kru

ppel

fam

ily

mem

ber G

LI3

guan

ine

nucl

eotid

e-

bind

ing

prot

ein

subu

nit

Gaq

(dar

k sk

in 1

, dar

k

skin

10)

11 1 7 11 3 7 2 13 19

Dar

k sk

in

Hyp

erpi

gmen

tatio

n of

digi

ts (p

olyd

acty

ly e

tc)

Ligh

ter s

kin

(man

y ot

her

defe

cts)

Hai

rless

. Wav

es o

f dar

k/

light

trav

el s

low

ly o

ver

skin

(pos

s. n

orm

al h

air

cycl

e +

very

sho

rt h

airs

)

Mic

roph

thal

mia

/

anop

htha

lmia

, pat

ches

of d

isco

lore

d or

whi

te fu

r

Man

y ab

norm

aliti

es

incl

udin

g lig

ht o

r silv

ered

coat

Ext

ra s

tem

-like

cel

ls in

hair

folli

cles

; abn

orm

al

hair,

irre

gula

r pig

men

t

depo

sitio

n

Whi

te b

elly

pat

ch o

r

lum

bar b

elt;

nerv

ous

syst

em d

efec

ts

(hom

ozyg

ous

post

nata

l

leth

al)

Dar

k sk

in

(hyp

erpr

olife

ratio

n of

mel

anoc

ytes

)

Gro

wth

fact

or re

cept

or

Tra

nscr

iptio

nfa

ctor

Gro

wth

fact

or re

cept

or

Tra

nscr

iptio

n fa

ctor

Ext

race

llula

r pro

tein

;

poss

ibly

epi

thel

ial–

mes

ench

ymal

inte

ract

ions

at b

asem

ent m

embr

ane

WN

T re

cept

or, p

utat

ivel

y

for W

NT

5A a

nd/o

r ND

P

(see

Ndp

)

Tra

nscr

iptio

n fa

ctor

Sig

nalin

g in

hed

geho

g

path

way

; mod

ifies

SO

X10

exp

ress

ion

Sig

nal t

rans

duct

ion,

poss

ibly

from

an

ED

NR

(s) t

o P

LCb

EG

FR

EN

1

FG

FR

2

FO

XN

1

FR

EM

2

FZ

D4

GA

TA

3

GLI

3

GN

AQ

N N Cro

uzon

syn

drom

e,

Pfe

iffer

syn

drom

e

N Fra

ser s

yndr

ome

Exu

dativ

e

vitr

eore

tinop

athy

1

Hyp

opar

athy

roid

ism

,

sens

orin

eura

l

deaf

ness

, and

rena

l

dise

ase

synd

rom

e,

Bar

akat

syn

drom

e

Pal

liste

r–H

all s

yndr

ome

and

othe

rs

Pos

sibl

e pl

atel

et d

efec

t

7p12

.3

2q14

.2

10q2

6

17q1

1.2

13q1

3.3

11q1

4.2

10p1

4

7p14

.1

9q21

Tab

le A

1.1

(Con

t’d)

Sym

bo

l (o

ld s

ymb

ol)

Nam

e (o

ld n

ame)

Mo

use

chro

mo

som

eM

uta

nt p

hen

oty

pe

Mo

lecu

lar/

bio

log

ical

fun

ctio

ns

Hu

man

sy

mb

ol

Hu

man

syn

dro

me

Hu

man

ch

rom

oso

me

9781405179546_4_001 2/23/10 2:04 PM Page 24

Gna

11 (D

sk7

)

Gpc

3

Gpr

161

(vl)

Hel

ls

Itgb1

Kit

(W)

Kitl

(Sl)

Krt

1 (D

sk12

)

Krt

2 (K

rt2-

17,D

sk2

)

Krt

4

Krt

17

Krt

75

guan

ine

nucl

eotid

e-

bind

ing

prot

ein

subu

nit

Ga1

1 (d

ark

skin

7)

glyp

ican

3, a

llele

tm1A

rge

G p

rote

in-c

oupl

ed

rece

ptor

161

(vac

uola

ted

lens

)

helic

ase,

lym

phoi

d

spec

ific

inte

grin

b1,

alle

le

tm1R

ef

Kit

onco

gene

(whi

te s

potti

ng)

Kit

ligan

d (s

teel

)

kera

tin 1

(dar

k sk

in 1

2)

kera

tin 2

(Ker

atin

2-17

, dar

k sk

in 2

)

kera

tin 4

kera

tin 1

7, a

llele

tm1C

ou

kera

tin 7

5, a

llele

tm1D

er

10 X 1 19 8 5 10 15 15 15 11 15

Dar

k sk

in

(hyp

erpr

olife

ratio

n of

mel

anoc

ytes

)

Dom

inan

t dis

tal a

nd b

elly

spot

ting

Vac

uola

ted

lens

,

occa

sion

al b

elly

spo

t,

spin

a bi

fida,

oth

ers

Ear

ly a

gein

g in

clud

es

gray

ing

by 1

5d o

ld.

p16

over

expr

essi

on

Tra

nsie

nt p

atch

y

hypo

pigm

enta

tion,

cre

st

mig

ratio

n de

fect

Whi

te s

potti

ng, a

nem

ia

and

germ

-cel

l defi

cien

cy

Whi

te s

potti

ng, a

nem

ia

and

germ

-cel

l defi

cien

cy

Dar

k sk

in

Dar

k sk

in

‘Brig

ht’ d

ilute

d co

at c

olor

Abn

orm

al h

airs

with

clus

tere

d m

elan

in

gran

ules

Hai

r def

ects

with

var

iabl

e

pigm

ent c

lum

ping

Sig

nal t

rans

duct

ion,

poss

ibly

from

an

ED

NR

(s)

GP

I-lin

ked

extr

acel

lula

r

mem

bran

e pr

otei

n;

puta

tive

SH

H-b

indi

ng

(com

petit

ive

with

PT

CH

)

Sig

nal t

rans

duct

ion

DN

A m

ethy

latio

n, g

ene

sile

ncin

g

Fib

rone

ctin

rece

ptor

–ce

ll

atta

chm

ent,

mig

ratio

n

Rec

epto

r for

KIT

ligan

d/st

em c

ell f

acto

r;

requ

ired

for m

elan

obla

st

surv

ival

Gro

wth

and

diffe

rent

iatio

n fa

ctor

Cyt

oske

leto

n

Cyt

oske

leto

n

Cyt

oske

leto

n

Cyt

oske

leto

n

Cyt

oske

leto

n

GN

A11

GP

C3

GP

R16

1

HE

LLS

ITG

B1

KIT

KIT

LG

KR

T1

KR

T2A

KR

T4

KR

T17

KR

T75

N Sim

pson

-Gol

abi-

Beh

mel

syn

drom

e

type

1

N N N Pie

bald

syn

drom

e

N Epi

derm

olyt

ic

hype

rker

atos

is

Icht

hyos

is b

ullo

sa o

f

Sie

men

s

Whi

te S

pong

e N

evus

of

Can

non

Pac

hyon

ychi

a

cong

enita

type

2

Ste

atoc

ysto

ma

mul

tiple

x

N

19p1

3

Xq2

6.2

1q24

.2

10q2

3.33

10p1

1.22

4q11

–q1

2

12q2

2

12q1

3

12q1

1–q1

3

12q1

3.13

17q1

.2

12q1

3.13

9781405179546_4_001 2/23/10 2:04 PM Page 25

Lef1

Lmx1

a (d

r)

Mbt

ps1

Mco

ln3

(Va

)

Mitf

(mi)

Mpz

l3 (r

c)

Myc

Not

ch1

Not

ch2

lym

phoi

d en

hanc

er

bind

ing

fact

or 1

, alle

le

tm1R

ugLI

M h

omeo

box

tran

scrip

tion

fact

or 1

a

(dre

her)

mem

bran

e-bo

und

tran

scrip

tion

fact

or

pept

idas

e, s

ite 1

,

alle

le w

rt

muc

olip

in 3

(var

itint

-wad

dler

)

mic

roph

thal

mia

-

asso

ciat

ed tr

ansc

riptio

n

fact

or (m

icro

phth

alm

ia)

mye

lin p

rote

in z

ero-

like

3 (a

llele

roug

h co

at)

mye

locy

tom

atos

is

onco

gene

(whe

n K

O

targ

eted

by

Wnt

1

prom

oter

-Cre

)

Not

ch g

ene

hom

olog

1

(Dro

soph

ila)

Not

ch g

ene

hom

olog

2

(Dro

soph

ila)

3 1 8 3 6 9 15 2 3

Und

erde

velo

ped

hair

folli

cles

lack

ing

mel

anin

Par

tial o

r com

plet

e w

hite

belt

and/

or b

elly

spo

t

Dilu

ted

hair

with

whi

te

base

(mel

anoc

yte

deat

h?)

Pat

ches

of n

orm

al, d

ilute

d

and

whi

te h

air (

and

beha

vior

al d

efec

ts)

Whi

te s

potti

ng a

nd s

mal

l

or a

bsen

t eye

s

Hai

r fol

licle

loss

, bla

ck

pigm

ent c

hang

es to

ligh

t

brow

n

Pig

men

tary

spo

tting

, not

head

Sca

ttere

d gr

ay h

airs

,

whe

n K

O ta

rget

ed to

mel

anoc

ytes

Sca

ttere

d gr

ay h

airs

,

whe

n K

O ta

rget

ed to

mel

anoc

ytes

;

all g

ray

with

Not

ch1

KO

,

even

tual

ly w

hite

Tra

nscr

iptio

n fa

ctor

;

Wnt

/b-c

aten

in m

edia

tor

Tra

nscr

iptio

n fa

ctor

Pep

tidas

e in

volv

ed in

regu

latio

n of

mem

bran

e

lipid

com

posi

tion

Cat

ion

chan

nel

Tra

nscr

iptio

n fa

ctor

:

mas

ter r

egul

ator

of

mel

anoc

yte

linea

ge

Put

ativ

e ad

hesi

on

prot

ein,

exp

ress

ed in

kera

tinoc

ytes

Tra

nscr

iptio

n fa

ctor

,

regu

lato

r of c

ell

prol

ifera

tion

Rec

epto

r for

liga

nds

in

Del

ta a

nd J

agge

d

fam

ilies

Rec

epto

r for

liga

nds

in

Del

ta a

nd J

agge

d

fam

ilies

LEF

1

LMX

1A

MB

TP

S1

MC

OLN

3

MIT

F

MP

ZL3

MY

C

NO

TC

H1

NO

TC

H2

Seb

aceo

us a

deno

mas

N N N Waa

rden

burg

synd

rom

e ty

pe 2

N N Ala

gille

Syn

drom

e 1

4q25

1q22

-23

16q2

3.3–

q24.

1

1p22

.3

3p12

-14

11q2

3.3

8q24

.21

9q34

.3

1p12

Tab

le A

1.1

(Con

t’d)

Sym

bo

l (o

ld s

ymb

ol)

Nam

e (o

ld n

ame)

Mo

use

chro

mo

som

eM

uta

nt p

hen

oty

pe

Mo

lecu

lar/

bio

log

ical

fun

ctio

ns

Hu

man

sy

mb

ol

Hu

man

syn

dro

me

Hu

man

ch

rom

oso

me

9781405179546_4_001 2/23/10 2:04 PM Page 26

Ntr

k1 (T

rkA

)

Pax

3 (S

p)

Pax

6 (S

ey)

Pcb

d1

Rb1

Rbp

j (R

BP

-JK

)

Sem

a3c

Sfx

n1 (f

)

Sna

i2

Sox

10 (D

om)

neur

otro

phic

tyro

sine

kina

se, r

ecep

tor,

type

1

paire

d bo

x ge

ne 3

(spl

otch

)

paire

d bo

x ge

ne 6

(sm

all e

ye)

pter

in 4

aca

rbin

olam

ine

dehy

drat

ase/

dim

eriz

atio

n co

fact

or

of h

epat

ocyt

e nu

clea

r

fact

or 1

a(T

CF

1)

retin

obla

stom

a 1

(tar

gete

d de

letio

n)

reco

mbi

natio

n si

gnal

bind

ing

prot

ein

for

imm

unog

lobu

lin k

J

regi

on (T

yr ta

rget

ed K

O)

sem

a do

mai

n,

imm

unog

lobu

lin d

omai

n

(Ig)

, sho

rt b

asic

dom

ain,

secr

eted

, (se

map

horin

)

3C Sid

erofl

exin

1 (fl

exed

tail)

Sna

il ho

mol

og 2

/Slu

g

SR

Y-b

ox-c

onta

inin

g

gene

10

(dom

inan

t

meg

acol

on)

3 1 2 10 14 5 5 13 16 15

Mot

tled

coat

(als

o ne

ural

defe

cts,

ski

n le

sion

s)

Whi

te b

elly

spl

otch

, neu

ral

cres

t def

ects

Eye

abn

orm

aliti

es c

an

incl

ude

redu

ced

RP

E,

also

dis

tal/

vent

ral w

hite

spot

ting

Mild

hyp

opig

men

tatio

n,

belly

spo

t, m

ild

mic

roph

thal

mia

Mel

anoc

yte

hype

rpro

lifer

atio

n in

cultu

re

Hai

r whi

teni

ng; o

ther

mel

anoc

ytes

not

affe

cted

Som

e sk

in

hypo

pigm

enta

tion,

ecto

pic

pigm

ent i

n in

tern

al

orga

ns

Bel

ly s

pot (

and

flexe

d ta

il,

anem

ia e

tc)

Spo

tting

, hea

d bl

aze,

pal

e

hair

and

skin

, neu

ral c

rest

and

othe

r org

an d

efec

ts

Whi

te s

potti

ng,

meg

acol

on a

nd o

ther

neur

al c

rest

def

ects

Cor

ecep

tor f

or n

erve

grow

th fa

ctor

Tra

nscr

iptio

n fa

ctor

Tra

nscr

iptio

n fa

ctor

Bot

h ph

enyl

alan

ine

met

abol

ism

and

bin

ding

part

ner o

f TC

F1

(HN

F1)

,

henc

e W

NT

pat

hway

inte

ract

ion

Gro

wth

-inhi

bito

r,

supp

ress

es E

2F

tran

sact

ivat

ion

activ

ity

Tra

nscr

iptio

n fa

ctor

,

med

iato

r of N

otch

sign

alin

g an

d ce

ll fa

te

Sec

rete

d si

gnal

ing

fact

or,

can

med

iate

axo

n

repu

lsio

n

Tric

arbo

xyla

te c

arrie

r

Tra

nscr

iptio

n fa

ctor

Tra

nscr

iptio

n fa

ctor

NT

RK

1

PA

X3

PA

X6

PC

BD

1

RB

1

RB

PJ

(RB

PS

UH

)

SE

MA

3C

SF

XN

1

SN

AI2

SO

X10

Inse

nsiti

vity

to p

ain,

cong

enita

l, w

ith

anhi

dros

is

Waa

rden

burg

synd

rom

e ty

pe 1

,

Waa

rden

burg

synd

rom

e ty

pe 3

Ani

ridia

Oth

er e

ye d

isor

ders

Hyp

erph

enyl

alan

inem

ia

with

prim

apte

rinur

ia

Ret

inob

last

oma

N N N Waa

rden

burg

synd

rom

e ty

pe 2

Waa

rden

burg

synd

rom

e ty

pes

2E, 4

1q23

.1

2q35

11p1

3

10q2

2.1

13q1

4.2

4p15

.2

7q21

.11

5q35

.3

8q11

22q1

3.1

9781405179546_4_001 2/23/10 2:04 PM Page 27

Suf

u

Tbx

10 (D

c)

Tbx

15 (d

e)

Tcf

ap2a

Tra

f6

Wnt

1

Wnt

3a

Zbt

b17

Zfp

53

Zic

2 (K

u)

supp

ress

or o

f fus

ed

hom

olog

( Dro

soph

ila)

T-b

ox 1

0 (D

ance

r)

T-b

ox 1

5 (d

roop

y ea

r)

tran

scrip

tion

fact

or

AP

-2a

Tnf

rece

ptor

-ass

ocia

ted

fact

or 6

Win

gles

s-re

late

d M

MT

V

inte

grat

ion

site

1

Win

gles

s-re

late

d M

MT

V

inte

grat

ion

site

3A

zinc

fing

er a

nd B

TB

dom

ain

cont

aini

ng 1

7

zinc

fing

er p

rote

in 5

3

Zin

c fin

ger p

rote

in o

f the

cere

bellu

m 2

(Kum

ba)

19 19 3 13 2 15 11 4 17 14

CN

S, d

ark

hair,

bas

al c

ell

lesi

ons

on s

kin.

(hed

geho

g pa

thw

ay

supp

ress

or)

Hea

d sp

ot (v

aria

ble)

; ear

,

pala

te a

nd n

eura

l def

ects

Ear

sha

pe; s

kele

tal,

alte

red

dors

oven

tral

col

or

patte

rn w

ith A

t , ae

Wnt

1-ta

rget

ed K

O g

ives

neur

al c

rest

def

ects

incl

udin

g pi

gmen

tary

Man

y ef

fect

s in

clud

ing

pale

ski

n, fe

w/d

elay

ed

hair

folli

cles

; pos

tnat

al

leth

al

Def

ects

of n

eura

l cre

st

incl

udin

g m

elan

obla

sts

in

mic

e la

ckin

g bo

th W

nt1

and

Wnt

3a

Def

ects

of n

eura

l cre

st

incl

udin

g m

elan

obla

sts

in

mic

e la

ckin

g bo

th W

nt1

and

Wnt

3a

Dar

kene

d co

at (m

ixed

stra

in b

ackg

roun

d); d

ark

skin

, dar

k de

rmis

aro

und

hairs

. Abn

orm

al fo

llicl

es

Abn

orm

al s

kin

pigm

enta

tion

Bel

ly s

pot,

curly

tail,

hind

brai

n

Cyt

opla

smic

sig

nalin

g

inte

rmed

iate

Tra

nscr

iptio

n fa

ctor

(ect

opic

exp

ress

ion

in D

c)

Tra

nscr

iptio

n fa

ctor

Tra

nscr

iptio

n fa

ctor

Sig

nalin

g fr

om IL

1A to

NF

-kB

Gro

wth

fact

or/m

orph

ogen

Gro

wth

fact

or/m

orph

ogen

Tra

nscr

iptio

n fa

ctor

Res

embl

es tr

ansc

riptio

n

fact

or

Tra

nscr

iptio

n fa

ctor

SU

FU

TB

X10

TB

X15

TF

AP

2A

TR

AF

6

WN

T1

WN

T3A

ZB

TB

17

? ZIC

2

Med

ullo

blas

tom

a

N N N Ect

oder

mal

dys

plas

ia,

anhi

drot

ic

N N N N Hol

opro

senc

epha

ly 5

10q2

4.32

11q1

3.2

1p13

6p24

11p1

2

12q1

3

1q42

1p36

.13

? 13q3

2

Tab

le A

1.1

(Con

t’d)

Sym

bo

l (o

ld s

ymb

ol)

Nam

e (o

ld n

ame)

Mo

use

chro

mo

som

eM

uta

nt p

hen

oty

pe

Mo

lecu

lar/

bio

log

ical

fun

ctio

ns

Hu

man

sy

mb

ol

Hu

man

syn

dro

me

Hu

man

ch

rom

oso

me

9781405179546_4_001 2/23/10 2:04 PM Page 28

(B) D

evel

op

men

t: p

red

om

inan

tly

eye

and

/or

ear

Bm

pr1a

Bm

pr1b

Fkb

p8

Gas

1

Gnp

at

Grlf

1

Jmjd

6

Mab

21l2

Med

1

Ndp

Nf1

bone

mor

phog

enet

ic

prot

ein

rece

ptor

,

type

1A

, alle

le tm

1Bh

bone

mor

phog

enet

ic

prot

ein

rece

ptor

,

type

1B

, alle

le tm

1Km

lF

K50

6 bi

ndin

g pr

otei

n 8,

alle

le tm

1Tili

grow

th a

rres

t spe

cific

1,

alle

le tm

1Fan

glyc

eron

epho

spha

te

O-a

cyltr

ansf

eras

e,

alle

le tm

1Jus

tgl

ucoc

ortic

oid

rece

ptor

DN

A b

indi

ng fa

ctor

1

(p19

0 R

hoG

AP

)

Jum

onji

dom

ain

cont

aini

ng 6

, alle

le

tm1G

bfM

ab-2

1-lik

e 2

(Cae

norh

abdi

tisel

egan

s), a

llele

tm1N

aom

edia

tor c

ompl

ex

subu

nit 1

Nor

rie d

isea

se h

omol

og

(alle

le tm

1Wbr

g)

neur

ofibr

omat

osis

1

14 3 8 13 8 7 11 3 11 X 11

Abn

orm

al p

rena

tal R

PE

with

dis

cont

inui

ty in

pigm

enta

tion

Abn

orm

al p

rena

tal R

PE

with

dis

cont

inui

ty in

pigm

enta

tion

Mic

roph

thal

mia

/

anop

htha

lmia

RP

E tr

ansd

iffer

entia

tes

to

neur

al re

tina

Abn

orm

al R

PE

mor

phol

ogy,

mic

roph

thal

mia

RP

E h

yper

plas

ia,

mic

roph

thal

mia

Lack

of o

ne/b

oth

eyes

,

ecto

pic

RP

E in

nos

e

lack

of R

PE

by

time

of

embr

yoni

c le

thal

ity

Low

retin

al p

igm

enta

tion

(bef

ore

embr

yoni

c

leth

ality

)

Man

y de

fect

s in

clud

ing

hype

rpig

men

tatio

n of

RP

E a

nd o

verg

row

th o

f

stria

l mel

anoc

ytes

Sm

all,

unpi

gmen

ted

eyes

,

mic

roph

thal

mia

(Ras

path

way

)

Rec

epto

r

Rec

epto

r

End

ogen

ous

calc

ineu

rin

inhi

bito

r; c

an in

hibi

t

apop

tosi

s

Can

enh

ance

hed

geho

g

sign

alin

g, in

hibi

t gro

wth

Enz

yme

Tra

nscr

iptio

nal r

epre

ssor

Dem

ethy

late

s hi

ston

es;

tran

scrip

tiona

l reg

ulat

or

Cel

l fat

e de

term

inat

ion,

TG

Fb

sign

alin

g

Bin

ds m

ethy

late

d D

NA

;

DN

A re

pair

TG

Fb-li

ke e

xtra

cellu

lar

fact

or; F

ZD

4 an

d LR

P5

also

ass

ocia

ted

with

hum

an N

orrie

dis

ease

Ras

GT

Pas

e-ac

tivat

ing

prot

ein

(neu

rofib

rom

in)

BM

PR

1A

BM

PR

1B

FK

BP

8

GA

S1

GN

PA

T

GR

LF1

JMJD

6

MA

B21

L2

MB

D4

ND

P

NF

1

Juve

nile

pol

ypos

is

synd

rom

e

Bra

chyd

acty

ly,

type

s A

2, C

;

chon

drod

yspl

asia

N Hol

opro

senc

epha

ly

Rhi

zom

elic

chon

drod

yspl

asia

punc

tata

, Typ

e 2

N N N N Nor

rie d

isea

se

Neu

rofib

rom

atos

is 1

10q2

2.3

4q23

–q2

4

19p1

3.11

9q21

.33

1q42

.2

19q1

3.32

17q2

5.2

4q31

.3

17q1

2

Xp1

1.4

17q1

1.2

9781405179546_4_001 2/23/10 2:04 PM Page 29

Nr2

e1 (f

rc)

Otx

2

Pax

2

Pdg

fb

Pdg

fc

Pha

ctr4

(hum

dy)

Pitx

3 (a

k)

Pyg

o1

Rs1

S1p

r2 (E

dg5

)

nucl

ear r

ecep

tor

subf

amily

2, g

roup

E,

mem

ber 1

(alle

le fi

erce

)

orth

oden

ticle

hom

olog

2

(Dro

soph

ila)

paire

d bo

x ge

ne 2

plat

elet

der

ived

gro

wth

fact

or, B

pol

ypep

tide

plat

elet

-der

ived

gro

wth

fact

or, C

pol

ypep

tide

phos

phat

ase

and

actin

regu

lato

r 4, a

llele

hum

pty

dum

pty

paire

d-lik

e

hom

eodo

mai

n

tran

scrip

tion

fact

or 3

pygo

pus

1

retin

osch

isis

(X-li

nked

,

juve

nile

) 1 (h

uman

),

alle

le tm

gc1

sphi

ngos

ine-

1-

phos

phat

e re

cept

or 2

10 14 19 15 3 4 19 9 X 9

Bra

in a

nd e

ye d

efec

ts;

asym

met

rical

and

mot

tled

RP

E

Man

y ef

fect

s in

clud

ing

RP

E h

yper

plas

ia

Man

y ef

fect

s in

clud

ing

RP

E c

ells

ext

endi

ng in

to

optic

ner

ve

Car

diov

ascu

lar a

nd e

ye

defe

cts

incl

ude

abno

rmal

RP

E, m

icro

phth

alm

ia

Dep

igm

ente

d sp

ots

in th

e

retin

a

Neu

robl

ast o

verg

row

th;

outg

row

ths

in R

PE

Eye

abn

orm

aliti

es

incl

udin

g

hype

rpig

men

tatio

n

arou

nd e

mbr

yoni

c pu

pil

Eye

and

oth

er d

efec

ts

incl

udin

g fo

lded

RP

E

Sm

all p

atch

es o

f

depi

gmen

tatio

n in

RP

E

Ear

def

ects

incl

ude

thic

keni

ng a

nd

hype

rpig

men

tatio

n of

str

ia

vasc

ular

is

Tra

nscr

iptio

nal

repr

esso

r, re

crui

ts H

DA

C

to D

NA

, ste

m c

ell

mai

nten

ance

Hox

-like

tran

scrip

tion

fact

or, c

an in

duce

RP

E

iden

tity

in n

eura

l ret

ina

Tra

nscr

iptio

n fa

ctor

Gro

wth

fact

or

Gro

wth

fact

or

Reg

ulat

or o

f pro

tein

phos

phat

ase

1 an

d its

deph

osph

oryl

atio

n of

RB

1

Tra

nscr

iptio

n fa

ctor

; CN

S

neur

onal

diff

eren

tiatio

n

Cof

acto

r for

b-c

aten

in- L

EF

-med

iate

d

tran

scrip

tion

Ret

inal

pro

tein

;

hom

olog

ies

to

cell-

adhe

sion

pro

tein

s

Rec

epto

r

NR

2E1

OT

X2

PA

X2

PD

GF

B

PD

GF

C

PH

AC

TR

4

PIT

X3

PY

GO

1

RS

1

S1P

R2

(ED

G5

)

N Dys

gnat

hia

com

plex

N Men

ingi

oma

N N Con

geni

tal c

atar

act

N Ret

inos

chis

is 1

,

X-li

nked

, juv

enile

N

6q21

14q2

3.1

10q2

4.31

22q1

3.1

4q32

.1

1p35

.3

10q2

4.32

15q2

1.3

Xp2

2.13

19p1

3.2

Tab

le A

1.1

(Con

t’d)

Sym

bo

l (o

ld s

ymb

ol)

Nam

e (o

ld n

ame)

Mo

use

chro

mo

som

eM

uta

nt p

hen

oty

pe

Mo

lecu

lar/

bio

log

ical

fun

ctio

ns

Hu

man

sy

mb

ol

Hu

man

syn

dro

me

Hu

man

ch

rom

oso

me

9781405179546_4_001 2/23/10 2:04 PM Page 30

Sem

a4a

Tim

p3

Tub

Unc

119

Vsx

2

(C) C

om

po

nen

ts o

f mel

ano

som

es a

nd

thei

r p

recu

rso

rs

Dct

(slt

)

Gpn

mb

Si (

si)

Slc

24a5

sem

a do

mai

n,

imm

unog

lobu

lin d

omai

n

(Ig)

, tra

nsm

embr

ane

dom

ain

(TM

) and

sho

rt

cyto

plas

mic

dom

ain,

(sem

apho

rin) 4

A

tissu

e in

hibi

tor o

f

met

allo

prot

eina

se 3

tubb

y ca

ndid

ate

gene

unc-

119

hom

olog

(Cae

norh

abdi

tisel

egan

s)vi

sual

sys

tem

hom

eobo

x 2

dopa

chro

me

taut

omer

ase

(sla

ty,

TR

P2)

glyc

opro

tein

(tra

nsm

embr

ane)

NM

B

silv

er (g

p100

, gp8

7,

Pm

el-1

7 et

c)

solu

te c

arrie

r fam

ily 2

4,

mem

ber a

5 (N

CK

X5)

3 10 7 11 12 14 6 10 2

Abn

orm

al R

PE

, pos

tnat

al

depi

gmen

tatio

n of

eye

Abn

orm

al R

PE

mor

phol

ogy

Obe

se; e

ye a

nd e

ar

abno

rmal

ities

;

dege

nera

tion

and

loss

of

RP

E

Ret

inal

deg

ener

atio

n;

mot

tling

of R

PE

Mic

roph

thal

mia

, red

uced

eye

pigm

enta

tion

Dilu

tion

of e

umel

anin

colo

r

Gla

ucom

a, ir

is p

igm

ent

epith

eliu

m d

isor

ders

,

espe

cial

ly w

ith T

yrp1

b/b

Silv

erin

g w

ith p

ostn

atal

mel

anoc

yte

loss

in

eum

elan

ic a

nim

als

(var

ying

with

str

ain

back

grou

nd)

Ski

n, e

ye c

olor

Tra

nsm

embr

ane

juxt

acrin

e si

gnal

ing

prot

ein

Pro

teas

e in

hibi

tor a

nd

can

bloc

k V

EG

F b

indi

ng

to re

cept

or

Ant

i-apo

ptot

ic;

dow

nstr

eam

med

iato

r of

Ga

qsi

gnal

ing

Pro

pose

d re

cept

or-

asso

ciat

ed a

ctiv

ator

of

SR

C-f

amily

kin

ases

Pax

-like

tran

scrip

tion

fact

or

Mel

anos

omal

enz

yme

App

aren

t mel

anos

omal

com

pone

nt

Mel

anos

ome

mat

rix;

trap

ping

of m

elan

in

inte

rmed

iate

s?

Cal

cium

tran

spor

ter,

?mel

anos

omal

SE

MA

4A

TIM

P3

TU

B

UN

C11

9

VS

X2

DC

T

GP

NM

B

SIL

V

SLC

24A

5

Ret

initi

s pi

gmen

tosa

Fun

dus

dyst

roph

y,

pseu

doin

flam

mat

ory,

of S

orsb

y

N N Cor

neal

dys

trop

hy,

kera

toco

nus

N N N Ski

n, h

air,

eye

col

or

1q22

22q1

2.3

11p1

5.4

17q1

1.2

14q

13q3

1–q3

2

7p15

12q1

3–q1

4

15q2

1.1

9781405179546_4_001 2/23/10 2:04 PM Page 31

Tab

le A

1.1

(Con

t’d)

Sym

bo

l (o

ld s

ymb

ol)

Nam

e (o

ld n

ame)

Mo

use

chro

mo

som

eM

uta

nt p

hen

oty

pe

Mo

lecu

lar/

bio

log

ical

fun

ctio

ns

Hu

man

sy

mb

ol

Hu

man

syn

dro

me

Hu

man

ch

rom

oso

me

Slc

45a2

(uw

,Mat

p)

Tyr

(c)

Tyr

p1 (b

)

(D) M

elan

oso

me

con

stru

ctio

n/p

rote

in r

ou

tin

g (H

PS

-rel

ated

)

Ap3

b1 (

pe)

Ap3

d (m

h)

Blo

c1s3

(rp

)

Cno

(cno

)

solu

te c

arrie

r fam

ily 4

5,

mem

ber a

2 (u

nder

whi

te,

mem

bran

e-as

soci

ated

tran

spor

ter p

rote

in)

tyro

sina

se (c

olor

,

albi

no)

tyro

sina

se-r

elat

ed

prot

ein

1 (b

row

n, T

RP

1)

adap

tor-

rela

ted

prot

ein

com

plex

AP

-3, b

1

subu

nit (

pear

l)

adap

tor-

rela

ted

prot

ein

com

plex

AP

-3, d

elta

subu

nit (

moc

ha)

biog

enes

is o

f lys

osom

e-

rela

ted

orga

nelle

s

com

plex

1, s

ubun

it 3

(red

uced

pig

men

tatio

n)

capp

ucci

no

15 7 4 13 10 7 5

Sev

ere

dilu

tion

of c

oat

and

eye

pigm

ent

No

pigm

ent i

n nu

ll m

ice

Bro

wn

eum

elan

in. A

llele

isa

can

cont

ribut

e to

glau

com

a

Pig

men

tary

dilu

tion

Pig

men

tary

dilu

tion

Pig

men

tary

dilu

tion

Pig

men

tary

dilu

tion

Sol

ute

tran

spor

ter

Mel

anos

omal

enz

yme

Mel

anos

omal

enz

yme

Org

anel

lar p

rote

in

rout

ing

Org

anel

le b

ioge

nesi

s;

AP

-3 c

ompo

nent

Org

anel

le b

ioge

nesi

s;

BLO

C1

com

pone

nt

Org

anel

le b

ioge

nesi

s;

BLO

C1

com

pone

nt

SLC

45A

2

TY

R

TY

RP

1

AP

3B1

[HP

S2]

AP

3D1

BLO

C1S

3

CN

O

Ocu

locu

tane

ous

albi

nism

type

4

Ocu

locu

tane

ous

albi

nism

type

1

Ocu

locu

tane

ous

albi

nism

type

3;

glau

com

a-re

late

d

pigm

ent d

ispe

rsio

n

synd

rom

e

Her

man

sky–

Pud

lak

synd

rom

e, ty

pe 2

N Her

man

sky–

Pud

lak

synd

rom

e, ty

pe 8

N

5p 11q2

1

9p23

5q14

.2

19p1

3.3

19q1

3.32

4p16

-p15

9781405179546_4_001 2/23/10 2:04 PM Page 32

Dtn

bp1

(sdy

)

Fig

4 (p

lt1)

Gpr

143

(Oa1

)

Hps

1 (e

p)

Hps

3 (c

oa)

Hps

4 (le

)

Hps

5 (r

u2)

Hps

6 (r

u)

Lyst

(bg

)

dyst

robr

evin

bin

ding

prot

ein

1 (s

andy

,

dysb

indi

n)

FIG

4 ho

mol

og

(Sac

char

omyc

esce

revi

siae

) (pa

le

trem

or);

phos

phat

idyl

inos

itol-

(3,5

)-bi

spho

spha

te

5-ph

osph

atas

e

G-p

rote

in-c

oupl

ed

rece

ptor

(GP

R14

3);

mou

se h

omol

og o

f

hum

an o

cula

r alb

inis

m 1

Her

man

sky–

Pud

lak

synd

rom

e 1

hom

olog

(pal

e ea

r)

Her

man

sky–

Pud

lak

synd

rom

e 3

hom

olog

(coc

oa)

Her

man

sky–

Pud

lak

synd

rom

e 4

hom

olog

(ligh

t ear

)

Her

man

sky–

Pud

lak

synd

rom

e 5

hom

olog

(rub

y-ey

e 2)

Her

man

sky–

Pud

lak

synd

rom

e 6

hom

olog

(rub

y-ey

e)

lyso

som

al tr

affic

king

regu

lato

r (be

ige)

13 10 X 19 3 5 7 19 13

San

dy c

olor

ed c

oat,

plat

elet

def

ect

Pal

e co

lor w

ith tr

emor

Red

uced

eye

pigm

enta

tion,

gia

nt

mel

anos

omes

Pal

e sk

in, s

light

coa

t

dilu

tion,

gia

nt

mel

anos

omes

; pla

tele

t

defe

ct

Hyp

opig

men

tatio

n,

plat

elet

def

ect

Pal

e sk

in, s

light

coa

t

dilu

tion,

gia

nt

mel

anos

omes

; pla

tele

t

defe

ct

Pig

men

tary

dilu

tion

and

red

eyes

; pla

tele

t def

ect

Pig

men

tary

dilu

tion

and

red

eyes

; pla

tele

t def

ect

Pal

e co

at,

imm

unod

efici

ency

Org

anel

le b

ioge

nesi

s;

BLO

C1

com

pone

nt

End

osom

e-ly

soso

me

axis

; clu

mpe

d

mel

anos

omes

(+im

mun

e

effe

cts,

etc

.)

Mel

anos

ome

biog

enes

is

and

size

; sig

nal

tran

sduc

tion

Org

anel

le b

ioge

nesi

s

and

size

; BLO

C3

com

pone

nt

Org

anel

le b

ioge

nesi

s;

BLO

C2

com

pone

nt

Org

anel

le b

ioge

nesi

s

and

size

; BLO

C3

com

pone

nt

Org

anel

le b

ioge

nesi

s;

BLO

C2

com

pone

nt

Org

anel

le b

ioge

nesi

s;

BLO

C2

com

pone

nt

Org

anel

le b

ioge

nesi

s

and

size

DT

NB

P1

FIG

4

OA

1

HP

S1

HP

S3

HP

S4

HP

S5

HP

S6

LYS

T

Her

man

sky–

Pud

lak

synd

rom

e, ty

pe 7

Cha

rcot

-Mar

ie-T

ooth

dise

ase

Ocu

lar a

lbin

ism

1

(Net

tlesh

ip-F

alls

)

Her

man

sky–

Pud

lak

synd

rom

e, ty

pe 1

Her

man

sky–

Pud

lak

synd

rom

e, ty

pe 3

Her

man

sky–

Pud

lak

synd

rom

e, ty

pe 4

Her

man

sky–

Pud

lak

synd

rom

e, ty

pe 5

Her

man

sky–

Pud

lak

synd

rom

e, ty

pe 6

Che

diak

-Hig

ashi

synd

rom

e

6p22

.3

6q21

Xp2

2.3

10q2

4

3q24

22q1

1–q1

2

11p1

4

10q2

4.31

1q42

9781405179546_4_001 2/23/10 2:04 PM Page 33

Oca

2 (p

)

Pld

n (p

a)

Rab

38 (c

ht)

Rab

ggta

(gm

)

Tra

ppc6

a

Txn

dc5

(mu

)

Vps

33a

(bf)

(E) M

elan

oso

me

tran

spo

rt

Mlp

h (ln

)

Mre

g (d

su,W

dt2

)

Myo

5a (d

)

Myo

7a (s

h-1)

Rab

27a

(ash

)

ocul

ocut

aneo

us

albi

nism

2 (p

ink-

eyed

dilu

tion)

palli

din

(pal

lid)

RA

B38

, mem

ber R

AS

onco

gene

fam

ily

(cho

cola

te)

Rab

ger

anyl

gera

nyl

tran

sfer

ase,

asu

buni

t

(gun

met

al)

traf

ficki

ng p

rote

in

part

icle

com

plex

6A

thio

redo

xin

dom

ain

cont

aini

ng 5

(mut

ed)

vacu

olar

pro

tein

sor

ting

33a

(buf

f)

mel

anop

hilin

(lea

den)

mel

anor

egul

in (d

ilute

supp

ress

or, w

hn-

depe

nden

t tra

nscr

ipt 2

)

myo

sin

Va

(dilu

te)

myo

sin

VIIa

(sha

ker-

1)

RA

B27

A, m

embe

r RA

S

onco

gene

fam

ily

(ash

en)

7 2 7 14 7 13 5 1 1 9 7 9

Sev

ere

loss

of e

umel

anin

in h

air,

ski

n an

d ey

es

Pal

e co

at, p

late

let d

efec

t

Bro

wn

eum

elan

in

Coa

t dilu

tion

Pal

e pa

tche

s in

the

coat

and

RP

E

Pal

e pi

gmen

t; pl

atel

et

defe

ct

Coa

t dilu

tion

Silv

ery

coat

dilu

tion,

mel

anos

omes

clu

ster

arou

nd n

ucle

us

Sup

pres

ses

dilu

te

phen

otyp

e (M

yo5a

d/d

)

Silv

ery

coat

dilu

tion,

mel

anos

omes

clu

ster

arou

nd n

ucle

us

Dea

fnes

s, b

alan

ce,

head

sha

king

Silv

ery

coat

dilu

tion,

mel

anos

omes

clu

ster

arou

nd n

ucle

us

?Glu

tath

ione

tran

spor

t in

ER

; mel

anos

omal

pro

tein

proc

essi

ng a

nd ro

utin

g

Org

anel

le b

ioge

nesi

s;

BLO

C1

com

pone

nt

Rou

ting

of T

yrp1

pro

tein

to m

elan

osom

e

Org

anel

le b

ioge

nesi

s

Pro

tein

traf

ficki

ng

Org

anel

le b

ioge

nesi

s;

BLO

C1

com

pone

nt

Org

anel

le b

ioge

nesi

s

Mel

anos

ome

tran

spor

t

Mel

anos

ome

tran

spor

t

(inte

ract

s w

ith M

yo5a

)

Mel

anos

ome

tran

spor

t

Mel

anos

ome

tran

spor

t

(pig

men

ted

retin

a; e

ar?)

Mel

anos

ome

tran

spor

t

OC

A2

PLD

N

RA

B38

RA

BG

GT

A

TR

AP

PC

6A

TX

ND

C5

VP

S33

A

MLP

H

MR

EG

MY

O5A

MY

O7A

RA

B27

A

Ocu

locu

tane

ous

albi

nism

type

2

N N Cho

roid

erem

ia

N N N N N Gris

celli

syn

drom

e

Ush

er s

yndr

ome,

type

1B

Gris

celli

syn

drom

e

15q1

1–q1

2

15q1

5.1

11q1

4

14q1

1.2

19q1

3.32

6p24

–p2

5

12q2

4.31

2q37

2q35

15q2

1

11q1

3.5

15q2

1

Tab

le A

1.1

(Con

t’d)

Sym

bo

l (o

ld s

ymb

ol)

Nam

e (o

ld n

ame)

Mo

use

chro

mo

som

eM

uta

nt p

hen

oty

pe

Mo

lecu

lar/

bio

log

ical

fun

ctio

ns

Hu

man

sy

mb

ol

Hu

man

syn

dro

me

Hu

man

ch

rom

oso

me

9781405179546_4_001 2/23/10 2:04 PM Page 34

(F) E

um

elan

in a

nd

ph

eom

elan

in

a Atr

n (m

g)

Drd

2

Eda

(Ta

)

Eda

radd

(cr)

Ggt

1

L1ca

m

Mc1

r (e)

Mgr

n1 (m

d)

Ost

m1

(Gl)

Pom

c

agou

ti (o

r non

agou

ti)

attr

actin

(mah

ogan

y)

dopa

min

e re

cept

or 2

,

alle

le tm

1mok

ecto

dysp

lasi

n-A

(tab

by)

ecto

dysp

lasi

n A

rece

ptor

-ass

ocia

ted

deat

h do

mai

n (c

rinkl

ed)

ggl

utam

yltr

ansp

eptid

ase

1 L1 c

ell a

dhes

ion

mol

ecul

e, a

llele

tm1S

or

mel

anoc

ortin

1 re

cept

or

(ext

ensi

on)

mah

ogun

in, r

ing

finge

r 1

(mah

ogan

oid)

oste

opet

rosi

s

asso

ciat

ed

tran

smem

bran

e

prot

ein

1 (G

rey-

leth

al)

pro-

opio

mel

anoc

ortin

-a

2 2 9 X 13 10 X 8 16 10 12

Diff

eren

t alle

les

alte

r

eum

elan

in/p

heom

elan

in

bala

nce,

eith

er w

ay

Phe

omel

anin

dar

kene

d

Ago

uti c

olor

dar

kene

d;

PO

MC

leve

l rai

sed

Dar

keni

ng o

f ago

uti

pigm

ent;

strip

ing

in +

/−fe

mal

es; d

efici

ent s

wea

t

glan

d an

d ha

ir

mor

phog

enes

is

Del

ayed

hai

r gro

wth

,

agou

ti co

at d

arke

r

dors

ally

, yel

low

er la

tera

lly

Red

uced

phe

omel

anin

Bla

ck fu

r pat

ches

on

agou

ti

Diff

eren

t alle

les

alte

r

eum

elan

in/p

heom

elan

in

bala

nce,

eith

er w

ay

Mel

anin

col

or, C

NS

effe

cts

Loss

of p

heom

elan

in;

oste

opet

rosi

s

Min

imal

or n

o ef

fect

on

phen

otyp

e in

bla

ck m

ice

Eum

elan

in/p

heom

elan

in

switc

h

Eum

elan

in/p

heom

elan

in

switc

h (a

mon

g ot

hers

)

Rec

epto

r

Mem

bran

e-bo

und,

?TN

F-r

elat

ed li

gand

Rec

epto

r

Glu

tath

ione

met

abol

ism

Cel

l adh

esio

n

Rec

epto

r

E3

ubiq

uitin

liga

se

Phe

omel

anin

and

oste

ocla

st fu

nctio

n

MS

H p

recu

rsor

AS

IP

AT

RN

DR

D2

ED

1

ED

AR

AD

D

GG

T lo

ci(s

ever

al)

L1C

AM

MC

1R

MG

RN

1

OS

TM

1

PO

MC

N N N Ect

oder

mal

dys

plas

ia,

anhi

drot

ic/h

ypoh

idro

tic

ecto

derm

al d

yspl

asia

N Glu

tath

ionu

ria

X-li

nked

hydr

ocep

halu

s,

MA

SA

/Cra

sh s

yndr

ome

Red

hai

r

N Sev

ere

rece

ssiv

e

oste

opet

rosi

s

Obe

sity

and

red

hair

20q1

1.2

20p1

3

1q23

.1–2

3.2

Xq1

2–q1

3

1q43

22q1

1

Xq2

8

16q2

4.3

16p1

3.3

6q21

2p23

.3

9781405179546_4_001 2/23/10 2:04 PM Page 35

Slc

7a11

(sut

)

Sm

arca

5

Sm

chd1

(Mom

meD

1)

Sox

2 (y

sb)

Sox

18 (r

g,D

cc1)

(G) S

yste

mic

eff

ects

Ato

x1

Atp

7a (M

o)

Atp

7b (t

x)

Bcl

2

solu

te c

arrie

r fam

ily 7

(cat

ioni

c am

ino

acid

tran

spor

ter,

y+

syst

em),

mem

ber 1

1 (s

ubtle

gra

y)

SW

I/SN

F re

late

d, m

atrix

asso

ciat

ed, a

ctin

depe

nden

t reg

ulat

or o

f

chro

mat

in, s

ubfa

mily

a,

mem

ber 5

, alle

le

Mom

meD

4

SM

C h

inge

dom

ain

cont

aini

ng 1

SR

Y-b

ox-c

onta

inin

g

gene

2 (y

ello

w

subm

arin

e)

SR

Y-b

ox-c

onta

inin

g

gene

18

(rag

ged,

dar

k

coat

col

or 1

)

Ant

ioxi

dant

pro

tein

1

hom

olog

1 (y

east

)

AT

Pas

e, C

u2+-

tran

spor

ting,

a

poly

pept

ide

(mot

tled)

AT

Pas

e, C

u2+-

tran

spor

ting,

b

poly

pept

ide

(tox

ic m

ilk)

B-c

ell

leuk

emia

/lym

phom

a 2

3 8 17 3 2 11 X 8 1

Req

uire

d fo

r nor

mal

pheo

mel

anin

leve

ls

Dom

inan

t mot

tled

coat

with

Ay /

−

Affe

cts

the

perc

enta

ge o

f

fem

ale

yello

w p

ups

on A

vy

back

grou

nd

Yel

low

hai

r, n

eura

l,

deaf

ness

Dar

k co

at in

ago

uti m

ice,

spar

se h

air

Hyp

opig

men

tatio

n

Pal

e fu

r in

hem

izyg

ous

mal

es, s

trip

ed in

hete

rozy

gous

fem

ales

Ear

ly g

rayi

ng, l

oss

of

mel

anoc

yte

stem

cel

ls

Cys

tine

tran

spor

ter

Tra

nscr

iptio

nal r

egul

ator

Mod

ifies

impr

intin

g,

X-in

activ

atio

n

Tra

nscr

iptio

n fa

ctor

;

Sox

2 re

gula

tes

Not

ch1

in e

ye

Tra

nscr

iptio

n fa

ctor

Cop

per t

rans

port

Cop

per t

rans

port

Cop

per t

rans

port

Inhi

bito

r of a

popt

osis

SLC

7A11

SM

AR

CA

5

SM

CH

D1

SO

X2

SO

X18

AT

OX

1

AT

P7A

AT

P7B

BC

L2

N N N Mic

roph

thal

mia

,

anop

htha

lmia

, neu

ral

and

pitu

itary

def

ects

N N Men

ke’s

dis

ease

Wils

on d

isea

se

B-c

ell l

ymph

oma

4 4q31

.1–

q31.

2

18p1

1.32

3q26

.33

20q1

3.33

5q32

Xq1

3.2–

q13.

3

13q1

4.3–

q21.

1

18q2

1.3

Tab

le A

1.1

(Con

t’d)

Sym

bo

l (o

ld s

ymb

ol)

Nam

e (o

ld n

ame)

Mo

use

chro

mo

som

eM

uta

nt p

hen

oty

pe

Mo

lecu

lar/

bio

log

ical

fun

ctio

ns

Hu

man

sy

mb

ol

Hu

man

syn

dro

me

Hu

man

ch

rom

oso

me

9781405179546_4_001 2/23/10 2:04 PM Page 36

Cas

p3D

st (d

t,ah

)

Elo

vl3

Elo

vl4

Erc

c2

Fas

Hep

h (s

la)

Hs2

st1

Oat

Pah

Pdp

k1

Pol

g

casp

ase

3, a

llele

tm1F

lvdy

ston

in, a

llele

dt-

J;(d

ysto

nia

mus

culo

rum

;

athe

toid

)

elon

gatio

n of

ver

y lo

ng

chai

n fa

tty a

cids

(FE

N1/

Elo

2,

SU

R4/

Elo

3, y

east

)-lik

e

3, a

llele

tm1J

aco

elon

gatio

n of

ver

y lo

ng

chai

n fa

tty a

cids

(FE

N1/

Elo

2, S

UR

4/

Elo

3, y

east

)-lik

e 4

exci

sion

repa

ir cr

oss-

com

plem

entin

g ro

dent

repa

ir de

ficie

ncy,

com

plem

enta

tion

grou

p 2

Fas

(TN

F re

cept

or

supe

rfam

ily m

embe

r 6)

heph

aest

in; s

ex-li

nked

anem

ia

hepa

ran

sulfa

te 2

-O-

sulfo

tran

sfer

ase

1

orni

thin

e

amin

otra

nsfe

rase

phen

ylal

anin

e

hydr

oxyl

ase

3-ph

osph

oino

sitid

e

depe

nden

t pro

tein

kina

se-1

, alle

le tm

1Bco

lpo

lym

eras

e (D

NA

dire

cted

), g

8 1 19 9 7 19 X 3 7 10 17 7

Abn

orm

al R

PE

Pal

e sk

in

Abn

orm

al h

airs

with

scat

tere

d

hype

rpig

men

tatio

n

Abn

orm

al re

tinae

incl

udin

g R

PE

UV

-sen

sitiv

ity, g

rayi

ng

hair,

redu

ced

lifes

pan

Few

er s

tria

l mel

anoc

ytes

on c

erta

in b

ackg

roun

d

abno

rmal

pig

men

t

loca

tion

in R

PE

Abn

orm

al R

PE

diffe

rent

iatio

n

Abn

orm

al R

PE

cel

l

mor

phol

ogy

Effe

cts

incl

ude

hypo

pigm

enta

tion,

wor

seni

ng w

ith a

ge

Abn

orm

al e

ye

pigm

enta

tion

Gen

eral

pre

mat

ure

agei

ng in

clud

ing

coat

gray

ing

Effe

ctor

of a

popt

osis

Enz

yme:

fatty

aci

d

bios

ynth

esis

Enz

yme:

fatty

aci

d

bios

ynth

esis

DN

A e

xcis

ion

repa

ir

Rec

epto

r med

iatin

g

apop

tosi

s

Reg

ulat

es ir

on le

vels

,

incl

udin

g in

RP

E

Enz

yme

in h

epar

an

sulfa

te b

iosy

nthe

sis

Enz

yme

Tyr

osin

e sy

nthe

sis

Pho

spho

ryla

tes

and

activ

ates

AK

T k

inas

e

DN

A p

olym

eras

e g

CA

SP

3D

ST

ELO

VL3

ELO

VL4

ER

CC

2

FA

S

HE

PH

HS

2ST

1

OA

T

PA

H

PD

PK

1

PO

LG

N N N Sta

rgar

dt D

isea

se 3

Xer

oder

ma

pigm

ento

sum

, gro

up D

tric

hoth

iody

stro

phy,

Coc

kayn

e sy

ndro

me

N N N Gyr

ate

atro

phy

Phe

nylk

eton

uria

N Alp

ers

synd

rom

e

4q35

.1

6p12

.1

10q2

4.32

6q14

.1

19q1

3

10q2

3.31

Xq1

2

1p22

.3

10q2

6.13

12q3

.2

16p1

3.3

15q2

6.1

9781405179546_4_001 2/23/10 2:04 PM Page 37

Pol

h

Pts

Rbp

1

Rpl

24 (B

st)

Rps

19 (D

sk3

)

Rps

20 (D

sk4

)

Rxr

a

Slc

31a1

Vld

lr

AC

TH

, adr

enoc

ortic

otro

phic

hor

mon

e, c

ortic

otro

pin;

AK

T, o

ncog

ene

isol

ated

from

tran

sfor

min

g m

urin

e re

trov

irus

AK

T8

foun

d in

a th

ymom

a ce

ll lin

e (=

RA

C=p

rote

in k

inas

e B

, PK

B);

CN

S, c

entr

al n

ervo

us s

yste

m;

ED

NR

, end

othe

lin re

cept

or; E

R, e

ndop

lasm

ic re

ticul

um; G

PI,

glyc

osyl

phos

phat

idyl

inos

itol;

HD

AC

, his

tone

dea

cety

lase

; KO

, kno

ckou

t; LE

F, l

ymph

oid-

enha

ncer

-bin

ding

fact

or; N

, non

e kn

own;

NF

-kB

, nuc

lear

fact

or

kB

; PLC

, pho

spho

lipas

e C

; PO

MC

, pro

-opi

omel

anoc

ortin

; RP

E, r

etin

al p

igm

ent e

pith

eliu

m; S

CF

, ste

m c

ell f

acto

r, a

lso

know

n as

Kit

ligan

d; T

GFb, t

rans

form

ing

grow

th fa

ctor

b; T

NF

, tum

or n

ecro

sis

fact

or;

UV

, ultr

avio

let;

VE

GF

, vas

cula

r end

othe

lial g

row

th fa

ctor

. We

are

grea

tly in

debt

ed to

the

Mou

se G

enom

e In

form

atic

s (M

GI)

and

Onl

ine

Men

delia

n In

herit

ance

in M

an (O

MIM

) web

site

s fo

r muc

h of

the

info

rmat

ion

pres

ente

d he

re (w

ww

.info

rmat

ics.

jax.

org/

, ww

w.n

cbi.n

lm.n

ih.g

ov/s

ites/

entr

ez?d

b=om

im).

A ta

ble

like

this

pla

ced

in a

boo

k w

ill in

evita

bly

beco

me

outd

ated

qui

te s

oon;

how

ever

, we

hope

that

upd

ated

info

rmat

ion

abou

t

the

mou

se c

olor

gen

es w

ill c

ontin

ue to

be

avai

labl

e at

the

IFP

CS

Col

or G

enes

reso

urce

(ww

w.e

spcr

.org

/mic

emut

). T

he s

ite a

lso

has

links

to h

uman

and

zeb

rafis

h or

thol

ogs,

and

to o

ther

use

ful r

esou

rces

.

poly

mer

ase

(DN

A

dire

cted

), h

(RA

D 3

0

rela

ted)

6-py

ruvo

yl-

tetr

ahyd

ropt

erin

synt

hase

retin

ol b

indi

ng p

rote

in 1

,

cellu

lar

ribos

omal

pro

tein

L24

(Bel

ly s

pot a

nd ta

il)

ribos

omal

pro

tein

S19

(Dar

k sk

in 3

)

ribos

omal

pro

tein

S20

(Dar

k sk

in 4

)

retin

oid

X re

cept

or a

solu

te c

arrie

r fam

ily 3

1,

mem

ber 1

very

low

den

sity

lipop

rote

in re

cept

or

17 9 9 16 7 4 2 4 19

Pig

men

t (m

elan

ocyt

e?)

accu

mul

atio

n in

ear

ski

n

follo

win

g U

V ir

radi

atio

n

Coa

t dilu

tion

(low

biop

terin

, hig

h P

he)

Abn

orm

al R

PE

mor

phol

ogy

Eye

, coa

t, sk

elet

al

Def

ect g

ives

p53

stab

iliza

tion

and

SC

F

[KIT

L] s

ynth

esis

in

kera

tinoc

ytes

, hen

ce d

ark

skin

with

ext

ra

mel

anoc

ytes

As

Rps

19

Pre

mat

ure

hair

gray

ing

then

hai

r los

s

Cop

per d

efici

ency

,

hypo

pigm

enta

tion

Thi

cken

ing

and

disr

uptio

n

of R

PE

DN

A p

olym

eras

e h

Tet

rahy

drob

iopt

erin

synt

hesi

s

Intr

acel

lula

r tra

nspo

rt o

f

retin

ol

Pro

tein

syn

thes

is

Pro

tein

syn

thes

is

Pro

tein

syn

thes

is

Ret

inoi

d re

cept

or

Reg

ulat

ion

of d

iver

se

path

way

s

Cop

per u

ptak

e in

to c

ells

Lipi

d up

take

into

cel

ls

PO

LH

PT

S

RB

P1

RP

L24

RP

S19

RP

S20

RX

RA

SLC

31A

1

VLD

LR

Xer

oder

ma

pigm

ento

sum

, var

iant

type

Phe

nylk

eton

uria

III

N N Dia

mon

d-B

lack

fan

anem

ia (D

BA

)

N N N Cer

ebel

lar h

ypop

lasi

a

and

men

tal r

etar

datio

n

6p21

.1

11q2

3.1

3q23

3q12

.3

19q1

3.2

8q12

.1

9q34

.2

9q32

9p24

.2

Tab

le A

1.1

(Con

t’d)

Sym

bo

l (o

ld s

ymb

ol)

Nam

e (o

ld n

ame)

Mo

use

chro

mo

som

eM

uta

nt p

hen

oty

pe

Mo

lecu

lar/

bio

log

ical

fun

ctio

ns

Hu

man

sy

mb

ol

Hu

man

syn

dro

me

Hu

man

ch

rom

oso

me

9781405179546_4_001 2/23/10 2:04 PM Page 38

Tab

le A

1.2

Sum

mar

y of

the

uncl

oned

mou

se c

olor

gen

es

Sym

bo

lN

ame

Ch

rom

oso

me

Eff

ect o

r p

oss

ible

fun

ctio

n

(A) D

evel

op

men

t?

Alm

ante

rior l

entic

onus

with

mic

roph

thal

mia

?D

efec

ts o

f eye

, coa

t, ot

hers

aoap

ampi

scho

?H

air l

oss

then

regr

owth

of d

arke

r, s

pars

er h

air

baln

2ba

lanc

e 2

?D

efec

ts o

f eye

, coa

t, ne

urol

ogic

alba

wbl

ack

and

whi

te18

Whi

te v

entr

um, s

catte

red

whi

te h

airs

dor

sally

Bsw

tbe

lly s

pot w

ith w

hite

toes

1B

elly

spo

t, w

hite

hin

d to

esbt

2be

lted

2?

Whi

te b

elt

crsp

cryp

torc

hidi

sm w

ith w

hite

spo

tting

5C

oat a

nd s

kin

pigm

ent,

mal

e re

prod

uctiv

e sy

stem

cwcu

rly w

hisk

ers

9C

BA

mic

e go

dar

ker.

(Som

e ly

mph

oma)

dds

dors

al d

ark

strip

e15

Dor

sal d

ark

strip

edk

dda

rken

ed d

orsa

l2

Dor

sal d

ark

strip

eD

ph1

DP

H1

hom

olog

11D

elay

ed e

mbr

yoni

c ey

e pi

gmen

tatio

nD

wh

disp

erse

d w

hite

hai

r2

Whi

te h

airs

and

pat

ches

thro

ugho

ut c

oat

Edn

rbm

1en

doth

elin

rece

ptor

type

B m

odifi

er 1

(QT

L)10

Mod

ifies

ext

ent o

f spo

tting

with

Edn

rbs

Eed

embr

yoni

c ec

tode

rm d

evel

opm

ent

7D

ilute

d co

at (d

war

fism

etc

)E

xma

exen

ceph

aly

and

seve

re m

icro

phth

alm

ia o

r ano

phth

alm

iaX

Pat

chy

coat

pig

men

tatio

n, m

icro

phth

alm

iafc

fleck

ing

2B

elly

spo

t, he

ad s

pot

Fk

fleck

?w

hite

on

belly

, tai

l, fe

etga

ndga

ndal

f?

Dilu

ted

coat

, +at

axia

etc

, del

ayed

leth

alG

nge

ntoo

10B

elly

spo

t, he

ad s

pot

Gsf

ali0

29gs

f abn

orm

al li

mbs

mut

ant 0

29?

Bel

ly s

pot,

poly

dact

yly

Gsf

ali1

9gs

f abn

orm

al li

mbs

mut

ant 0

19?

Bel

ly s

pot,

poly

dact

yly

Gsf

ali2

0gs

f abn

orm

al li

mbs

mut

ant 0

20?

Bel

ly s

pot,

poly

dact

yly

Gsf

dcc2

gsf d

ark

coat

col

our 2

?B

elly

spo

t, da

rker

coa

tG

sfkt

a19

gsf k

inke

d ta

il 19

?B

elly

spo

t, ki

nked

tail

Gsf

sco6

gsf s

potte

d co

at 6

?S

mal

l hea

d bl

aze

Gsf

sco7

gsf s

potte

d co

at 7

?D

ista

l dep

igm

enta

tion,

bel

ly s

pot,

whi

te v

ibris

sae

9781405179546_4_001 2/23/10 2:04 PM Page 39

Gsf

und3

gsf u

ndefi

ned

3?

Whi

te ri

ng a

roun

d ta

ilG

sfw

bs01

1gs

f whi

te b

elly

spo

t 011

?B

elly

spo

tG

sfw

bs1

gsf w

hite

bel

ly s

pot 1

?B

elly

spo

t, ki

nked

tail

Gsf

wbs

3gs

f whi

te b

elly

spo

t 3?

Larg

e be

lly s

pot

Gsf

wbs

5gs

f whi

te b

elly

spo

t 5?

Bel

ly s

pot

Gsf

wbs

9gs

f whi

te b

elly

spo

t 9?

Bel

ly s

pot

Gsf

wnw

gsf w

hite

nos

e an

d w

hisk

ers

?W

hite

nos

e an

d vi

bris

sae

Gsf

wt

gsf w

hite

tail

?W

hite

tail

Hpt

hair

patc

hes

4H

air p

atch

y an

d sk

in h

as p

atch

es o

f pig

men

t; al

so c

ardi

ovas

cula

r de

fect

s, e

tc.

hshe

ad s

pot

?H

ead

spot

Idc

iris

dysp

lasi

a w

ith c

atar

act

?E

ye a

bnor

mal

ities

, mic

roph

thal

mia

, bel

ly s

pot

Mtu

Mon

tu12

Few

er n

eura

l cre

st c

ells

; bel

ly s

pot,

curly

tail

Mw

fhm

odifi

er o

f whi

te fo

relo

ck h

ypop

igm

enta

tion

10M

odifi

es p

heno

type

of S

ox10

Dom

Pbd

lpi

ebal

d-lik

e?

Spo

tting

, pro

gres

sive

dilu

tion,

meg

acol

onP

hpa

tch

dele

tion

regi

on (p

atch

)5

Whi

te s

potti

ng; r

espo

nsib

le g

ene

in d

elet

ion

unce

rtai

n; n

ot P

dgfr

a;

but K

IT e

xpre

ssio

n is

alte

red

pwk

patc

hwor

k10

Pat

chw

ork

of p

igm

ente

d an

d un

pigm

ente

d ha

irs; a

utoc

rine

grow

th

of m

elan

ocyt

es?

rgro

tatin

g?

Ear

dev

elop

men

t, ne

ural

, som

etim

es b

elly

spo

tR

gsc5

8R

IKE

N G

enom

ic S

cien

ces

Cen

ter (

GS

C),

58

?W

hite

hai

rs, s

pots

or b

and

in d

orsa

l lum

bar r

egio

n, v

aryi

ng w

ith

gene

tic b

ackg

roun

dR

gsc1

17R

IKE

N G

enom

ic S

cien

ces

Cen

ter (

GS

C),

117

?B

elly

spo

t, do

med

sku

ll, d

omin

ant (

not a

ll m

ice)

Rgs

c257

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 2

57?

Sca

ttere

d w

hite

hai

rs d

orsa

llyR

gsc2

69R

IKE

N G

enom

ic S

cien

ces

Cen

ter (

GS

C),

269

?W

hite

dig

its a

nd ta

il tip

, som

e w

hite

pat

ches

on

belly

Rgs

c288

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 2

88?

Pat

ches

of p

aler

fur

Rgs

c394

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 3

94?

Var

iabl

e w

hite

dig

its a

nd ta

il tip

Rgs

c398

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 3

98?

Var

iabl

e w

hite

dig

its a

nd ta

il tip

Rgs

c444

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 4

44?

Var

iabl

e nu

mbe

r of w

hite

spo

ts o

n ta

il

Tab

le A

1.2

(Con

t’d)

Sym

bo

lN

ame

Ch

rom

oso

me

Eff

ect o

r p

oss

ible

fun

ctio

n

9781405179546_4_001 2/23/10 2:04 PM Page 40

Rgs

c510

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 5

10?

Var

iabl

e w

hite

dig

its a

nd ta

il tip

Rgs

c662

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 6

62?

Abn

orm

al d

igit

pigm

enta

tion

and

whi

te ta

il tip

Rgs

c713

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 7

13?

Whi

te d

ista

l fee

t and

tail

tip, s

omet

imes

bel

ly s

pot

Rgs

c755

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 7

55?

Whi

te to

e tip

s an

d ta

il tip

Rgs

c767

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 7

67?

Whi

te to

e tip

s an

d ta

il tip

Rgs

c990

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 9

90?

Whi

te to

e tip

s an

d ta

il tip

Rgs

c124

6R

IKE

N G

enom

ic S

cien

ces

Cen

ter (

GS

C),

124

6?

Coa

t dilu

tion

espe

cial

ly v

entr

ally

; som

e w

hite

spo

tting

.R

gsc1

461

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 1

461

?W

hite

bel

ly s

pot,

skel

etal

cha

nges

Rgs

c151

3R

IKE

N G

enom

ic S

cien

ces

Cen

ter (

GS

C),

151

3?

Dilu

tion

dors

ally

, gra

y fu

r ven

tral

ly (e

ven

in A

/−),

som

e be

lly s

potti

ngR

gsc1

520

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 1

520

?W

hite

dig

its, t

ail t

ip, b

elly

spo

tR

gsc1

545

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 1

545

?B

elly

spo

tR

gsc1

554

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 1

554

?B

elly

spo

tR

gsc1

658

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 1

658

?S

catte

red

whi

te h

airs

, som

e co

lor d

ilutio

nR

gsc1

742

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 1

742

?B

elly

spo

tR

gsc1

843

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 1

843

?V

aria

ble

scat

tere

d w

hite

spo

ts in

fem

ales

Rgs

c185

5R

IKE

N G

enom

ic S

cien

ces

Cen

ter (

GS

C),

185

5?

Bel

ly s

pot

rnro

an14

Mic

ro-s

potti

ng, w

hole

coa

trs

rece

ssiv

e sp

ottin

g5

Mic

ro-s

potti

ng (r

educ

ed m

elan

ocyt

e nu

mbe

rs);

inte

ract

s w

ith K

itrs

lkre

cess

ive

spot

ting-

like

5G

ray

coat

, hea

d an

d/o

r bel

ly s

pot,

whi

te s

pots

Shm

ush

amu

9W

hite

feet

, bel

ly s

pot,

head

spo

tS

ka7

skel

etal

/axi

al 7

?La

rge

belly

spo

t and

ske

leta

l def

ects

Skc

42sk

in/c

oat c

olor

42

?S

harp

ly d

elin

eate

d w

hite

bel

lyS

kc43

skin

/coa

t col

or 4

3?

Whi

te b

elly

pat

ch a

nd ta

ilsk

c44

skin

/coa

t col

or 4

4?

Whi

te b

elt,

som

etim

es s

potti

ngS

lsse

mid

omin

ant l

etha

l spo

tting

2S

emid

omin

ant s

potti

ng; m

ay b

e al

lelic

to E

dn3

smk

smok

y?

Gra

y co

at o

n a/

a, w

ith re

prod

uctiv

e sy

stem

def

ects

stn

stun

ted

19B

elly

spo

t, al

tere

d fa

cial

ske

leto

nS

tol

strip

y oi

lyX

Str

ipy

in h

eter

ozyg

ote,

dar

k in

hom

o- a

nd h

emiz

ygot

e;

oily

hai

r; m

icro

phth

alm

iaS

trx2

stria

ted,

X-li

nked

2X

Str

iped

fur,

thic

k sk

in in

+/−

, let

hal i

n −/

YS

trx3

stria

ted,

X-li

nked

3X

Str

iped

fur,

thic

k sk

in in

+/−

, let

hal i

n −/

YS

trx4

stria

ted,

X-li

nked

4X

Str

iped

fur,

sca

ly s

kin

in +

/−, l

etha

l in

−/Y

9781405179546_4_001 2/23/10 2:04 PM Page 41

Tcm

tota

l cat

arac

t with

mic

roph

thal

mia

4M

icro

phth

alm

ia, a

bnor

mal

iris

, len

s, re

tina

tga

tran

spos

ition

of t

he g

reat

art

erie

s4

Ect

opic

pig

men

tatio

n in

hea

rt a

nd th

orac

ic c

avity

tmgc

17T

enne

ssee

Mou

se G

enom

e C

onso

rtiu

m 1

7X

Bel

ly s

pot,

synd

acty

lyT

mgc

19T

enne

ssee

Mou

se G

enom

e C

onso

rtiu

m 1

9?

Bel

ly s

pot,

othe

r spo

tting

, pos

tnat

al d

omin

ant l

etha

lT

mgc

21T

enne

ssee

Mou

se G

enom

e C

onso

rtiu

m 2

1?

Bel

ly s

pot,

othe

r spo

tting

, whi

te fe

ettp

taup

e7

Dilu

ted

colo

r, fe

mal

e re

prod

uctiv

e sy

stem

Ts

tail-

shor

t11

Bel

ly s

pot,

whi

te d

ista

l for

elim

bs; d

efici

enci

es o

f ske

leto

n,

bloo

d, g

row

th, e

tc.

vsva

riabl

e sp

ottin

g9

Spo

tting

on

belly

, hea

d, ta

il, fe

etV

ssva

riabl

e sp

ot a

nd s

ize

2V

aria

ble

belly

spo

t, sm

all s

ize

Wbc

tw

hite

bel

ly, c

law

s an

d ta

il1

Var

iabl

e sp

ottin

g of

bel

ly, f

eet,

tail

Wht

ow

hite

toes

7C

olor

, dig

it de

velo

pmen

tw

nw

hite

nos

e15

Whi

te n

ose,

ven

tral

str

eak

Wtg

rw

avy

tiger

XC

oat s

trip

ed a

nd w

avy;

repr

oduc

tive

defe

cts

Xls

X-li

nked

str

ipe

XC

oat s

trip

ing,

1 w

hite

spo

t on

left

flank

Xs

extr

a-to

es s

potti

ng7

Col

or, d

igit

deve

lopm

ent

Xsl

extr

a-to

es s

potti

ng-li

ke7

Ext

ra to

es, b

elly

spo

t

(B) M

elan

ocy

te fu

nct

ion

on

ly?

brw

dbr

owno

id?

Mel

anin

col

or (b

row

n)C

al7

cara

cul-l

ike

715

Pal

e sk

in a

nd e

yes

djdi

lutio

n Ja

pan

?P

ink

skin

, gra

y co

at (a

/a)

dpdi

lutio

n-P

eru

15P

ale

coat

plto

plat

ino

?O

ff-w

hite

coa

t, bl

ack

eyes

; not

Tyr

pow

der

pow

der

?P

ale

coat

rgsc

1820

RIK

EN

Gen

omic

Sci

ence

s C

ente

r (G

SC

), 1

820

?N

o pi

gmen

t, al

bino

Rgs

c190

4R

IKE

N G

enom

ic S

cien

ces

Cen

ter (

GS

C),

190

4?

Coa

t col

or d

ilutio

nru

2lru

by-e

ye 2

-like

7Li

ke ru

2; g

ray

coat

, pal

e sk

in, r

ed e

yes

Tab

le A

1.2

(Con

t’d)

Sym

bo

lN

ame

Ch

rom

oso

me

Eff

ect o

r p

oss

ible

fun

ctio

n

9781405179546_4_001 2/23/10 2:04 PM Page 42

sea

sepi

a1

Coa

t col

or d

ilutio

nsk

c14

skin

/coa

t col

or 1

4?

Pal

e co

atsk

c19

skin

/coa

t col

or 1

9?

Pal

e co

atsk

c21

skin

/coa

t col

or 2

1?

Pal

e co

at w

hen

youn

g; w

hite

gua

rd h

airs

skc2

2sk

in/c

oat c

olor

22

?P

ale

coat

whe

n yo

ung;

whi

te g

uard

hai

rs, r

ed e

yes

skc2

3sk

in/c

oat c

olor

23

?P

ale

coat

whe

n yo

ung;

dar

k re

d ey

essk

c28

skin

/coa

t col

or 2

8?

Silv

er c

oat

skc2

9sk

in/c

oat c

olor

29

?S

ilver

coa

tsk

c30

skin

/coa

t col

or 3

0?

Coa

t silv

erin

g, m

elan

ocyt

e de

ath

skc3

1sk

in/c

oat c

olor

31

?C

oat s

ilver

ing,

mel

anoc

yte

deat

hS

kc36

skin

/coa

t col

or 3

6?

Mot

tled

coat

in fe

mal

etit

anm

titan

ium

?P

ale

coat

tmgc

14T

enne

ssee

Mou

se G

enom

e C

onso

rtiu

m 1

4?

Dilu

ted

coat

Tm

gc18

Ten

ness

ee M

ouse

Gen

ome

Con

sort

ium

18

?D

ilute

d co

at, d

omin

ant

uwl

unde

rwhi

te-li

ke15

Rub

y-ey

ed c

ream

; pos

sibl

e uw

(Slc

45a2

) alle

le

(C) E

um

elan

in a

nd

ph

eom

elan

in?

Cdi

fco

lor d

iffer

ence

(QT

L)15

Mod

ifies

yel

low

coa

t col

orda

dark

7P

heom

elan

in d

efici

ent

dal

dark

-like

7Li

ke d

ark

din

dens

e in

ciso

rs16

Loss

of p

heom

elan

in/w

hite

bel

ly o

n ag

outi

back

grou

nd; l

oss

yello

w

on e

ars

Dm

yaq1

dark

er m

odifi

catio

n of

yel

low

ago

uti Q

TL

11

Dar

keni

ng o

f yel

low

and

ago

uti c

oats

Dm

yaq2

dark

er m

odifi

catio

n of

yel

low

ago

uti Q

TL

21

Dar

keni

ng o

f yel

low

and

ago

uti c

oats

Dm

yaq3

dark

er m

odifi

catio

n of

yel

low

ago

uti Q

TL

315

Dar

keni

ng o

f yel

low

and

ago

uti c

oats

dwg

dwar

f gre

y10

Mul

tiple

effe

cts,

incl

udin

g de

ficie

nt p

heom

elan

in, o

steo

clas

tsgd

ngo

lden

?E

umel

anin

defi

cien

tgr

griz

zled

10P

heom

elan

in d

efici

ent;

tail

gri

grey

inte

nse

11P

heom

elan

in d

efici

ent

gtgr

ay tr

emor

(pro

babl

y ex

tinct

)15

Phe

omel

anin

defi

cien

t; sp

ottin

g, n

euro

logi

cal

Och

ochr

e4

Defi

cien

t eum

elan

in, b

alan

ce, o

ther

9781405179546_4_001 2/23/10 2:04 PM Page 43

Phe

oph

eom

elan

in (Q

TL)

15M

odifi

es c

olor

of A

y /−

mic

e; m

ore

eum

elan

ic a

llele

dom

inan

tR

eph8

redu

ced

pheo

mel

anin

8?

Ago

uti m

ice

dark

ersk

c17

skin

/coa

t col

or 1

7?

Dar

k ba

ckU

umbr

ous

?D

orsa

l phe

omel

anin

dar

kene

dU

pum

brou

s-pa

ttern

ed?

Dor

sal p

heom

elan

in d

arke

ned

(pat

chy)

Ym

yello

w m

ottle

dX

Yel

low

mot

tling

, hem

izyg

ous

leth

alY

vye

llow

val

ue (Q

TL)

15M

odifi

er o

f eum

elan

in/p

heom

elan

in ra

tio

(D) O

rgan

elle

bio

gen

esis

or

tran

spo

rt?

dill

Dilu

te-li

ke?

Like

dilu

terg

sc80

RIK

EN

Gen

omic

Sci

ence

s C

ente

r, 8

0?

Dilu

ted

coat

, int

erac

ts w

ith M

yo5a

d

skc6

skin

/coa

t col

or 6

?P

ale

coat

, lys

osom

al s

tora

ge d

efec

t, lo

ng h

air

skc9

skin

/coa

t col

or 9

?P

ale

coat

, lys

osom

al s

tora

ge d

efec

tsk

c10

skin

/coa

t col

or 1

0?

Pal

e co

at, l

ysos

omal

sto

rage

def

ect

skc1

2sk

in/c

oat c

olor

12

?P

ale

coat

, lys

osom

al s

tora

ge d

efec

tsk

c15

skin

/coa

t col

or 1

5?

Pal

e sk

in

(E) D

ark

skin

Dfp

dark

foot

pad

s?

Dar

k sk

inD

fp2

dark

foot

pad

s 2

4D

ark

skin

Dsk

6da

rk s

kin

63

Dar

k sk

inD

sk8

dark

ski

n 8

3D

ark

skin

Dsk

9da

rk s

kin

911

Dar

k sk

inR

gsc4

5R

IKE

N G

enom

ic S

cien

ces

Cen

ter,

45

?G

ray-

pigm

ente

d fo

otpa

ds w

ith th

icke

ned

epid

erm

isR

gsc6

3R

IKE

N G

enom

ic S

cien

ces

Cen

ter,

63

?S

light

ly d

ark

hind

foot

pads

Rgs

c150

RIK

EN

Gen

omic

Sci

ence

s C

ente

r, 1

50?

Dar

k fo

otpa

dsR

gsc1

83R

IKE

N G

enom

ic S

cien

ces

Cen

ter,

183

?D

ark

foot

pads

Tab

le A

1.2

(Con

t’d)

Sym

bo

lN

ame

Ch

rom

oso

me

Eff

ect o

r p

oss

ible

fun

ctio

n

9781405179546_4_001 2/23/10 2:04 PM Page 44

Rgs

c194

RIK

EN

Gen

omic

Sci

ence

s C

ente

r, 1

94?

Slig

htly

dar

k fo

otpa

dsR

gsc2

07R

IKE

N G

enom

ic S

cien

ces

Cen

ter,

207

?P

igm

ente

d de

rmat

ogly

phs

of fo

otpa

dsR

gsc3

72R

IKE

N G

enom

ic S

cien

ces

Cen

ter,

372

?D

ark

foot

pads

Rgs

c515

RIK

EN

Gen

omic

Sci

ence

s C

ente

r, 5

15?

Dar

k fo

otpa

dsR

gsc5

26R

IKE

N G

enom

ic S

cien

ces

Cen

ter,

526

?D

ark

foot

pads

Rgs

c715

RIK

EN

Gen

omic

Sci

ence

s C

ente

r, 7

15?

Slig

htly

dar

k fo

otpa

dsS

kc39

skin

/coa

t col

or 3

9?

Dar

k sk

inS

kc41

skin

/coa

t col

or 4

1 (b

lack

foot

)?

Dar

k sk

inso

oso

oty

foot

2D

ark

skin

(F) U

nkn

ow

n

Dlp

1do

min

ant l

ight

ened

pig

men

t 1?

Ligh

ter c

oat,

som

etim

es s

light

bel

ly s

pot

Dlp

2do

min

ant l

ight

ened

pig

men

t 2?

Ligh

ter c

oat

Dlp

3do

min

ant l

ight

ened

pig

men

t 3?

Muc

h lig

hter

coa

tfe

fade

d6

Pro

gres

sive

coa

t fad

ing

fnld

fain

t lin

edX

Hem

izyg

ous

leth

al; fi

ne d

orsa

l str

ipin

gF

wfa

wn

?Li

ghte

ns R

nm

utan

t mic

ege

grei

ge1

Pal

er c

oat a

nd s

kin

in d

ilute

, bro

wn

mic

eG

sfbc

c2gs

f brig

ht c

oat c

olou

r 2?

Com

plex

coa

t col

or v

aria

tion

lgr

Lond

on g

rey

?G

ray

coat

, sys

tem

ic e

ffect

sLg

t (Li

)lig

ht?

Ligh

t coa

t (do

min

ant)

, lig

ht s

kin

(rec

essi

ve)

Lilin

edX

Hem

izyg

ous

leth

al; fi

ne s

trip

ing;

del

etio

n th

at in

clud

es R

sk2

Mch

mod

ifier

of c

hinc

hilla

?T

yrc-

chm

ice

look

bro

wne

rM

chm

1m

odifi

er o

f chi

nchi

lla-m

ottle

d 1

?Li

ghte

ns T

yrc-

mm

ice

Mch

m2

mod

ifier

of c

hinc

hilla

-mot

tled

2?

Ligh

tens

Tyr

c-m

mic

eM

fsm

utan

t fur

is s

trip

ed?

‘Str

iped

fur’

nmf1

92ne

uros

cien

ce m

utag

enes

is fa

cilit

y, 1

92?

Spo

tted

or m

ottle

d re

tinae

nur1

5ne

urol

ogic

al 1

5?

Dilu

ted

coat

(and

neu

ral e

ffect

s, e

arly

leth

al)

nur1

6ne

urol

ogic

al 1

6?

Dilu

ted

coat

(and

neu

ral e

ffect

s, e

arly

leth

al)

nur1

7ne

urol

ogic

al 1

7?

Dilu

ted

coat

(and

neu

ral e

ffect

s)R

d4re

tinal

deg

ener

atio

n 4

4E

ye d

efec

ts in

clud

e pi

gmen

ted

spot

s in

the

fund

us

9781405179546_4_001 2/23/10 2:04 PM Page 45

Rd9

retin

al d

egen

erat

ion

9X

Ret

ina

mot

tled

and

dege

nera

tes

rdp

redu

ced

pigm

ent (

not s

ame

as rp

/Blo

c1s3

)?

Mar

ked

pigm

ent d

ilutio

n, re

d ey

esR

gsc7

1R

IKE

N G

enom

ic S

cien

ces

Cen

ter,

71

?D

ilutio

n do

rsal

ly (d

omin

ant)

, gra

y be

lly, s

omet

imes

bel

ly s

pot

Rgs

c212

RIK

EN

Gen

omic

Sci

ence

s C

ente

r, 2

12?

Bla

ck ro

stra

lly a

nd b

row

n ca

udal

ly o

f a m

id-t

runk

dem

arca

tion

line

Rgs

c547

RIK

EN

Gen

omic

Sci

ence

s C

ente

r, 5

47?

Pat

ch o

f bro

wn

fur b

etw

een

the

eyes

, by

8 w

eeks

old

Rgs

c796

RIK

EN

Gen

omic

Sci

ence

s C

ente

r, 7

96?

Slig

ht c

oat d

ilutio

n (d

omin

ant)

and

beh

avio

ral c

hang

essk

c18

skin

/coa

t col

or 1

8?

Abn

orm

al c

oat c

olor

, sm

all s

ize

Skc

45sk

in/c

oat c

olor

45

?‘S

hadi

ng o

f coa

t in

anim

als

expe

cted

to b

e w

hite

’S

taau

toso

mal

str

ipin

gX

Str

ipin

g in

bot

h se

xes

Sta

2st

ripin

g, a

utos

omal

2?

Str

iped

coa

tS

ta3

strip

ing,

aut

osom

al 3

?S

trip

ed c

oat

Str

gst

riped

gre

asy

XH

air t

extu

re a

nd c

olor

tmgc

22T

enne

ssee

Mou

se G

enom

e C

onso

rtiu

m 2

27

Abn

orm

al R

PE

, cho

roid

tmgc

23T

enne

ssee

Mou

se G

enom

e C

onso

rtiu

m 2

37

RP

E h

yper

pigm

ente

d ar

ound

opt

ic d

isk

tmgc

25T

enne

ssee

Mou

se G

enom

e C

onso

rtiu

m 2

57

Abn

orm

al R

PE

, hyp

opig

men

ted

fund

ustm

gc29

Ten

ness

ee M

ouse

Gen

ome

Con

sort

ium

29

7Li

ke tm

gc25

wuf

whi

te u

nder

fur (

extin

ct?)

?U

nder

fur w

hite

Xm

o2X

-link

ed m

ottle

d 2

XM

ottle

d co

at; h

emiz

ygou

s le

thal

Xm

o3X

-link

ed m

ottle

d 3

XM

ottle

d co

at; h

emiz

ygou

s le

thal

Xm

o4X

-link

ed m

ottle

d 4

XM

ottle

d co

at; h

emiz

ygou

s po

stna

tal l

etha

l, pa

le c

oat

Xm

o5X

-link

ed m

ottle

d 5

XM

ottle

d co

at; h

emiz

ygou

s le

thal

Xm

o6X

-link

ed m

ottle

d 6

XM

ottle

d co

at; h

emiz

ygou

s le

thal

QT

L, q

uant

itativ

e tr

ait l

ocus

; RP

E, r

etin

al p

igm

ent e

pith

eliu

m. C

ateg

orie

s an

d fu

nctio

ns a

re g

ener

ally

pro

visi

onal

or s

pecu

lativ

e.

Tab

le A

1.2

(Con

t’d)

Sym

bo

lN

ame

Ch

rom

oso

me

Eff

ect o

r p

oss

ible

fun

ctio

n

9781405179546_4_001 2/23/10 2:04 PM Page 46

CHAPTER 1 INTRODUCTION TO THE PIGMENTARY SYSTEM 47

Figure 1.17 Studs Terkel, Mahonia, and Postdoc (left to right). Terk may have a mutationat the Silver locus (see Chapter 4). Mahonia is pheomelanic, often known as chestnut orsorrel (probable genotype Mc1r e/Mc1r e). Postdoc is the horse equivalent of wild type,known as bay or brown, depending on the amount of eumelanic pigment. Note that themane, tail, and legs are eumelanic, and the pheomelanic pigmentation on the body variesfrom bright red/yellow to dark and nearly eumelanic, in response to modifying genes.

9781405179546_4_001 2/23/10 2:04 PM Page 47

9781405179546_4_001 2/23/10 2:04 PM Page 48