Reviews in Endocrine & Metabolic Disorders 2000;1:265±274# 2000 Kluwer Academic Publishers. Manufactured in The Netherlands.

Clinical Spectrum and Pathogenesis ofPseudohypoparathyroidism

Michael A. LevineDivision of Pediatric Endocrinology, Department of Pediatrics,

The Johns Hopkins University School of Medicine

Key Words. pseudohypoparathyroidism, hormone resistance, Gproteins, imprinting, adenylyl cyclase

Introduction

Mammalian cells express a variety of signal transduction

mechanisms that enable them to respond to extracellular

stimuli. One highly conserved mechanism for transmem-

brane signal transduction is a modular system in which

heterotrimeric (a, b, g) guanine nucleotide binding

proteins (G proteins) act as ``couplers'' to associate

plasma membrane receptors with membrane-bound

effector enzymes and ion channels. Because alterations

in signal processing can in¯uence cellular growth and

function, and can often lead to disease, molecular and

biochemical characterization of G protein-coupled

signaling has progressed rapidly. Recent studies have

identi®ed germline and somatic mutations of G proteins

and heptahelical receptors as the basis of several human

disorders [1]. The most well-characterized G protein

defects have been mutations in the human GNAS1 gene

(20q13.11) that encodes the a subunit of Gs, the G

protein that stimulates adenylyl cyclase. Investigation of

naturally occurring GNAS1 mutations has provided

substantial insight into functional domains of Gas, and

in many instances has complemented or con®rmed

analyses of mutant a chains that were designed in the

research laboratory. For example, early laboratory

studies indicated that replacement of either arginine201

or glutamine227 of Gas inhibits the intrinsic GTPase

activity resulting in constitutive activation of adenylyl

cyclase and increased production of cAMP [2,3].

Subsequent human genetic analyses identi®ed identical

GNAS1 activating mutations that arose spontaneously in

a subset of pituitary and thyroid adenomas [4,5]. Similar

mutations have also been found in patients with the

McCune-Albright syndrome, a sporadic disorder char-

acterized by increased hormone production and/or

cellular proliferation of many tissues [6,7]. By contrast,

germline mutations of the GNAS1 gene that decrease

expression or function of Gas are present in subjects with

Albright hereditary osteodystrophy (AHO [8]), an

autosomal dominant disorder associated with a con-

stellation of developmental defects. Most patients with

AHO also show reduced responsiveness to parathyroid

hormone (PTH) and other hormones whose receptors

require Gas to activate adenylyl cyclase, a condition

termed pseudohypoparathyroidism (PHP) type Ia.

Remarkably, in many families patients with PHP type

Ia have relatives who have AHO and apparently normal

hormonal responsiveness despite identical loss of

function GNAS1 mutations. This variant is termed

pseudopseudohypoparathyroidism ( pseudoPHP) [9], an

awkward designation that was chosen to draw attention

to the physical similarities but biochemical differences to

PHP type Ia.

The spectrum of pseudohypoparathyroidism extends

to include subjects who lack features of AHO and who

have normal expression of Gas in accessible tissues.

These variants include both PHP type Ib and PHP type II,

which differ signi®cantly in their molecular pathophy-

siology (Table 1). Clinical and biochemical analyses of

subjects with the various forms of PHP have expanded

our understanding of the developmental and functional

consequences of dysfunctional G protein-coupled sig-

naling pathways, and have provided unexpected insights

into the importance of cAMP as a regulator of the growth

and/or function of many tissues. This review will focus

on the pathophysiology of PHP, and integrate basic

biological defects with their clinical implications.

Address correspondence to: Michael A. Levine, MD, Professor

of Pediatrics, Medicine and Pathology, The Johns Hopkins

University School of Medicine, Park Bldg. Room 211, 600 N. Wolfe

Street, Baltimore, MD 21287. E-mail: mlevine@jhmi.edu

265

PTH Resistance

Fuller Albright and his associates ®rst described the

failure of several unusual patients with biochemical

features of hypoparathyroidism (i.e., hypocalcemia and

hyperphosphatemia) to show either a calcemic or a

phosphaturic response to administered parathyroid

extract [10]. Albright termed this disorder ``pseudo-

hypoparathyroidism'' (PHP), and speculated that the

primary defect resided in the inability of peripheral

tissues to respond appropriately to PTH. Characterization

of the molecular basis for PHP commenced with the

observation that cAMP mediates many of the actions of

PTH on kidney and bone, and that administration of

biologically active PTH to normal subjects leads to a

signi®cant increase in the urinary excretion of nephro-

genous cAMP [11]. The PTH infusion test remains the

most reliable test available for the diagnosis of PHP, and

enables distinction between the several variants of the

syndrome (Table 1). Thus, patients with PHP type I fail

to show an appropriate increase in urinary excretion of

both cAMP and phosphate [11], while subjects with a far

less common form, PHP type II, show a normal increase

in urinary cAMP excretion but have an impaired

phosphaturic response [12]. Subjects with pseudoPHP

have a normal urinary cAMP response to PTH [11,13],

which distinguishes them from occasional patients with

PHP type Ia who are able to maintain normal serum

levels of calcium and phosphorous without treatment

[14].

It has been generally assumed that bone cells in

patients with PHP type I are innately resistant to PTH,

but this remains unproved. In fact, cultured bone cells

from a patient with PHP type I have been shown to

increase intracellular cAMP normally in response to PTH

treatment in vitro [15]. Moreover, clinical, roentgeno-

graphic, or histologic evidence of increased bone

turnover and demineralization occurs in some patients

with PHP type I [16]. Evidence that bone cells are

unresponsive to PTH is largely inferred from the

observation that hypocalcemic patients with PHP type I

fail to show a calcemic response after administration of

PTH. However, it is likely that reduced circulating levels

of 1,25(OH)2D account for the lack of a calcemic

response to PTH in patients with PHP type I [17].

PTH Signaling and G Proteins

PTH resistance may derive either from a failure of the

hormone to generate appropriate intracellular second

messengers or from a lack of response to these

intracellular effectors. PTH generates intracellular

signals via activating of a transmembrane transduction

system that is composed of at least three plasma

membrane-bound components: receptors that detect

extracellular signals, intracellular effector proteins that

can generate second messengers, and heterotrimeric G

proteins that couple the activated receptors to speci®c

effector proteins (reviewed in Neer [18]) (Fig. 1). The

classical PTH receptor that is expressed in bone and

kidney is a * 75-kD glycoprotein that is often referred to

as the PTH/PTHrP or type 1 PTH receptor (PTH1R) [19].

The PTH1R binds PTH and parathyroid hormone-related

protein (PTHrP), a factor made by diverse tumors that

cause humorally-mediated hypercalcemia, with equiva-

lent af®nity, and can activate both adenylyl cyclase and

phospholipase C. In addition to the classical type 1 PTH

Table 1. Classi®cation of the various forms of pseudohypoparathyroidism based on clinical, biochemical, and genetic features

PHP type Ia PseudoPHP PHP type Ib PHP type Ic PHP type II

Physical appearance Albright hereditary

osteodystrophy typical, but

may be subtle or (rarely)

absent

Normal Albright

hereditary

osteodystrophy

Normal

Response to PTH

Urine cAMP Defective Normal Defective Defective Normal

Urine phosphorous Defective Normal Defective Defective Defective

Serum calcium level Low or (rarely) Normal normal Low Low Low

Hormone resistance Generalized Absent Limited to

PTH target

tissues

Generalized Limited to

PTH target

tissues

Gas activity Reduced Reduced Normal Normal Normal

Inheritance Autosomal dominant Autosomal

dominant

(most cases)

Unknown Unknown

Molecular defect Heterozygous mutations in the

GNAS1 gene

Unknown

(20q13.1?)

Unknown Unknown

266 Levine

receptor, two other receptor proteins, termed the type 2

and type 3 PTH receptors, with unique characteristics,

have been identi®ed. The type 2 PTH receptor (PTH2R)

is not expressed in conventional PTH target tissues (i.e.,

bone and kidney), and interacts only with PTH [20,21].

By contrast, the type 3 receptor (PTH3R) preferentially

binds PTHrP, and can activate adenylyl cyclase but not

phospholipase C [22]. All three PTH receptors are

members of a large family of receptors that bind

hormones, neurotransmitters, cytokines, light photons,

taste and odor molecules. These receptors consist of a

single polypeptide chain that is predicted by hydro-

phobicity plots to span the plasma membrane seven times

(i.e., heptahelical), forming three extracellular and three

or four intracellular loops and a cytoplasmic carboxyl-

terminal tail.

G proteins share a common heterotrimeric structure

consisting of an a subunit and a tightly coupled bg dimer.

The a subunit interacts with detector and effector

molecules, binds GTP, and possesses intrinsic GTPase

activity [23]. In mammals sixteen genes encode a family

of some 20 a chains that can be grouped into four major

classes (Gs, Gi, Gq, G12) according to structural and

functional homologies (Table 2). The distribution of

some a subunits is highly tissue speci®c (e.g., Gaolf is

restricted to olfactory neuroepithelium), while other achains have a ubiquitous representation (e.g., Gas is

expressed in all tissues). The GTP-liganded a chain is the

primary regulator of membrane-bound ion channels and

enzymes that generate intracellular ``second messen-

gers.'' The a subunits associate with a smaller group of b(at least 6) and g (at least 12) subunits [24]. Speci®c band g subunits combine preferentially with one another

Fig. 1. Cell surface receptors for PTH are coupled to two classes ofG proteins. Gs mediates stimulation of adenylyl cyclase (AC) and theproduction of cAMP, which in turn activates protein kinase A (PKA).Gq stimulates phospholipase C (PLC) to form the second messengersinositol-(1,4,5)-trisphosphate (IP3) and diacylglycerol (DAG) frommembrane bound phosphatidylinositol-(4,5)-bisphosphate. IP3

increases intracellular calcium (Ca2�) and DAG stimulates proteinkinase C (PKC) activity. Each G protein consists of a unique a chainand a bg dimer.

Table 2. Classi®cation of G protein and chains

Subfamily Members Physiological activators Effectors

Gs as b-adrenergic amines, parathyroid

hormone, thyrotropin, corticotropin,

glucagon, others

: adenylyl cyclase

: calcium channels

aolf Odorant molecules : adenylyl cyclase

Gi ai1, ai2, ai3 a2-adrenergic amines, muscarinic

M2, neurotransmitters, others

; adenylyl cyclase

: potassium channels

; calcium channels

at1 light photons (rods) : cGMP phosphodiesterase

at2 light photon (cones)

agust tastant molecules : cyclic nucleotide phosphodiesterase

ao a2-adrenergic, met enkaphalin : phospholipase C

az Muscarinic, others ; adenylyl cyclase

Gq aq a1-adrenergic amines and M1

muscarinic, others

: phospholipase Cb1

a11

a14

a15=16

G12 a12 Thrombin, others Na�, H� antiporter, cytoskeleton ?

a13

Pseudohypoparathyroidism 267

[25,26] and the resultant bg dimers can associate with

different a subunits to create a panoply of heterotrimeric

G proteins. Combinatorial speci®city in the associations

between various G protein subunits provides the

potential for enormous diversity, and may allow distinct

heterotrimers to interact selectively with only a limited

number of the more than 1000 G protein-coupled

receptors. At present it is unknown whether particular

G protein subunit associations occur randomly or if there

are regulated mechanisms that determine the subunit

composition of heterotrimers.

The activation state of the heterotrimeric G protein is

regulated by a mechanism in which the binding and

hydrolysis of GTP acts as a molecular timing switch

(Fig. 2). In the basal (inactive) state, G proteins exist in

the heterotrimeric form with GDP bound to the a chain.

The association of a with bg occludes the sites of

interaction of both of these molecules with downstream

effector molecules, and the inactive state is maintained

by an extremely slow rate of dissociation of GDP from

the a chain �K&0:01=min�. The interaction of a ligand-

bound receptor with a G protein facilitates the release of

tightly bound GDP from the a chain and the subsequent

binding of cytosolic GTP. The binding of GTP to the achain induces conformational changes that facilitate the

dissociation of a-GTP from the bg dimer and the

receptor. The free a-GTP chain has 20 to 100-fold

higher af®nity for target enzymes and ion channels than

the a-GDP chain. Early work had suggested that only the

free a-GTP chain could regulate downstream signaling,

and that the bg dimers served only to localize the a chain

to the plasma membrane. However, more recent studies

have shown that bg dimers can also participate in

downstream signaling events through interaction with a

wide array of targets [27,28]; for example, bg dimers can

in¯uence activity of certain forms of adenylyl cyclase

and phospholipase C, open potassium channels, partici-

pate in receptor desensitization, mediate mitogen-

activated protein (MAP) kinase phosphorylation, and

modulate leukocyte chemotaxis.

G protein activity is regulated by an intrinsic GTPase

that hydrolyzes GTP to GDP and thereby provides a

molecular timing switch that controls the duration, and

thereby the intensity, of the signaling event. Hydrolysis

of a-GTP to a-GDP leads to dissociation of the a chain

from effector molecules and promotes reassociation with

G protein bg dimers, thus preventing further interaction

of these subunits with downstream effectors and

readying the heterotrimeric G protein for another round

of receptor-activated signaling. The GTPase reaction is a

high-energy transition state in which the amino acids

arginine201 and glutamine227 in Gas act as ``®ngers'' to

position the g-phosphate of GTP near the oxygen of a

water molecule. The intrinsic rates of GTP hydrolysis by

G protein a chains differ widely, and interactions that

in¯uence the rate of the GTPase reaction can have

profound consequences. Several factors can act as

``GTPase activating proteins'' or GAP's [29], to

accelerate the slow �kcat&4=min� intrinsic rate of GTP

hydrolysis by Ga proteins. For example, RGS proteins

(for ``regulators of G protein signaling'') can stimulate a

40-fold increase in the catalytic rate of GTP hydrolysis of

some a chains, and thus can markedly accelerate the

termination of G protein signaling [30] (Fig. 2).

PHP type Ia and PseudoPHP

Subjects with PHP type Ia or pseudoPHP typically

manifest a characteristic constellation of developmental

defects, termed Albright hereditary osteodystrophy

(AHO), that includes short stature, obesity, a round

face, brachy-dactyly, subcutaneous ossi®cation, and mild

to moderate mental retardation (Fig. 3) [9,10].

Considerable variability occurs in the clinical expression

of these features even among affected members of a

single family, and all of these features may not be present

in every case [31]. On rare occasion, it may be

Fig. 2. The cycle of hormone-dependent GTP binding and hydrolysisthat regulates heterotrimeric G protein signal transduction. In thenon-stimulated, basal (Off ) state, GDP is tightly bound to the a chainof the heterotrimeric G protein. Binding of an agonist (ligand) to itsreceptor (depicted with seven transmembrane spanning domains)induces a conformational change in the receptor, and enables it toactivate the G protein. The G protein now releases GDP and bindsGTP present in the cytosol. The binding of GTP to the a chain leadsto dissociation of the a-GTP from the bg dimer, and each of thesemolecules is now free to regulate downstream effector proteins (e.g.,AC, adenylyl cyclase). The hydrolysis of GTP to GDP by the intrinsicGTPase of the a chain promotes reassociation of a-GDP with bg andthe inactive state is restored. The heterotrimeric G protein is readyfor another cycle of hormone-induced activation.

268 Levine

impossible to detect any features of AHO in an individual

with Gas de®ciency [32].

Obesity is a common feature of AHO and about one

third of all patients with AHO are above the 90th

percentile of weight for their age, despite their short

stature [33] (Fig. 3). Patients with AHO typically have a

round face, a short neck, and a ¯attened bridge of the

nose. Numerous other abnormalities of the head and neck

have also been noted. Dental abnormalities are common

in subjects with PHP type Ia and include dentin and

enamel hypoplasia, short and blunted roots, and delayed

or absent tooth eruption [34].

Brachydactyly is the most reliable sign for the

diagnosis of AHO, and may be symmetrical or

asymmetrical and involve one or both hands or feet

(Fig. 3). Shortening of the distal phalanx of the thumb is

the most common abnormality; this is apparent on

physical exam as a thumb in which the ratio of the width

of the nail to its length is increased (so called ``Murder's

thumb'' or ``potter's thumb''). Shortening of the

metacarpals causes shortening of the digits, particularly

the 4th and 5th. Shortening of the metacarpals may also

be recognized on physical exam as dimpling over the

knuckles of a clenched ®st (Archibald sign, Fig. 3C).

Often a de®nitive diagnosis requires careful examination

of radiographs of the hands and feet (Fig. 3B). A speci®c

pattern of shortening of the bones in the hand has been

identi®ed, in which the distal phalanx of the thumb and

third through ®fth metacarpals are the most severely

shortened [35,36]. This may be useful in distinguishing

AHO from other unrelated syndromes in which

brachydactyly occurs, such as familial brachydactyly,

Turner syndrome, and Klinefelter syndrome [35]. The

skeletal abnormalities of AHO may not be apparent until

a child is ®ve years old [37].

Patients with AHO develop heterotopic ossi®cations

of the soft tissues or skin (osteoma cutis) that are

unrelated to abnormalities in serum calcium or phos-

phorous levels. Osteoma cutis is present in 25% to 50%

of cases of AHO, and may be the presenting feature of

AHO in infancy or childhood. Subcutaneous ossi®cation

may occur in the absence of hypocalcemia or other

features of AHO [38,39]. Blue-tinged, stony hard papular

or nodular lesions can occur anywhere, and may appear

to be migratory on repeated exams [38]. Biopsy of these

lesions reveals heterotopic ossi®cation with spicules of

mineralizing osteoid and calci®ed cartilage.

De®ciency of Gas in patients with PHP type Ia is

associated with resistance to multiple hormones,

including PTH, TSH, gonadotropins, and glucagon,

whose effects are mediated by cAMP [40]. Primary

hypothyroidism occurs in most patients with PHP Type

Ia [40]. Typically, patients lack a goiter or anti-thyroid

antibodies and have an elevated serum TSH with an

exaggerated response to TRH. Serum levels of T4 may be

low or low normal. Hypothyroidism may occur early in

life prior to the development of hypocalcemia, and

elevated serum levels of TSH are not uncommonly

detected during neonatal screening [41]. Unfortunately,

early institution of thyroid hormone replacement does

not seem to prevent the development of mental

retardation [42].

Reproductive dysfunction occurs commonly in sub-

jects with PHP type Ia. Women may have delayed

puberty, oligomenorrhea, and infertility [40,43]. Plasma

gonadotropins may be elevated, but are more commonly

normal. Some patients show an exaggerated serum

gonadotropin response to gonadotropin releasing hor-

mone (GnRH) [44,45]. Features of hypogonadism may

be less obvious in men.

Abnormal hormone responsiveness may occur in

some tissues without obvious clinical sequelae. For

example, the hepatic glucose response to glucagon is

Fig. 3. Typical features of Albright hereditary osteodystrophy.Panel A. A young woman with characteristic features of AHO; notethe short stature, disproportionate shortening of the limbs, obesity,and round face. Panel B. Radiograph of patient's hand showingmarked shortening of 4th and 5th metacarpals. Panel C. Archibaldsign, the replacement of ``knuckles'' with ``dimples'' due to themarked shortening of the metacarpal bones. Panel D. Brachydactylyof the hand, note thumb sign (``Murderer's thumb'' or ``potter'sthumb'') and shortening of the 4th and 5th digits.

Pseudohypoparathyroidism 269

normal although plasma cAMP concentrations fail to

increase normally [40,46]. In other tissues signi®cant

hormone resistance does not occur despite the apparent

reduction in Gas. Diabetes insipidus is not a feature of

AHO, and urine is concentrated normally in response to

vasopressin in patients with PHP type Ia [47].

The discovery that Gas de®ciency results from

inactivating mutations in the GNAS1 gene, located at

20q13.2?13.3 [48], provided con®rmation of autosomal

dominant transmission of the molecular defect in AHO

and resolved longstanding controversies regarding the

inheritance of this disorder [8,49±51]. GNAS1 is a

complex gene [52] comprised of at least 16 exons,

including 3 alternative ®rst exons [53,54]. Alternative

splicing of nascent transcripts derived from exons 1±13

generates four mRNA's that encode Gas. Deletion of

exon 3 results in the loss of 15 codons from the mRNA,

while use of an alternative splice site in exon 4 results in

the insertion of a single additional codon into the mRNA.

This produces two Gas proteins with apparent molecular

weights of 45 kDa and two isoforms of apparent

molecular weights of 52 kDa [52] that exhibit speci®c

patterns of tissue expression [55]. Both long and short

forms of Gas can stimulate adenylyl cyclase and open

calcium channels [56], but biochemical characterization

of these isoforms has revealed subtle differences in the

binding constant for GDP, the rate at which the forms are

activated by agonist binding, ef®ciency of adenylyl

cyclase stimulation, and the rate of GTP hydrolysis. The

signi®cance of these differences remains unknown

[56,57], but these distinctions imply the existence of as

yet unknown roles for these G proteins [58].

Additional complexity in the processing of the

GNAS1 gene derives from the use of alternative ®rst

exons that generate novel transcripts. Because these

proteins lack amino acid sequences encoded by exon 1,

which are required for interaction of Gas with Gbg and

attachment to the plasma membrane, it is unlikely that

these proteins can function as transmembrane signal

transducers. In one case, a Gas transcript is produced

with an alternative ®rst exon that lacks an initiator ATG;

thus, a truncated, non-functional Gas protein is translated

from an inframe ATG in exon 2 [59]. The role of this Gas

chain is unknown. In two other instances unique

transcripts are generated using additional coding exons

that are present upstream of the exon 1 used to generate

functional Gas protein. The more 50 of these exons

encodes the neuroendocrine secretory protein NESP55, a

chromogranin-like protein, and is generated from a

transcript that contains sequences derived from exon 2 of

GNAS1 in the 30 nontranslated region [60,61].

Accordingly, NESP55 shares no protein homology with

Gas. The more downstream alternative exon encodes a

51 kDa protein, and when spliced inframe to exons 2±13

results in a transcript that generates a larger Gas isoform

that is termed XLas [62]. Both NESP55 and XLas have

been implicated in regulated secretion in neuroendocrine

tissues.

Molecular studies of DNA from subjects with PHP

type Ia and their relatives with pseudoPHP have

disclosed a wide range of inactivating mutations in the

GNAS1 gene that account for a 50% reduction in

expression or function of Gas protein (reviewed in

reference [63]; Fig. 4). All patients are heterozygous, and

have one normal GNAS1 allele and one defective allele.

Defects include missense mutations, point mutations that

disrupt ef®cient splicing or terminate translation prema-

turely, and small deletions. Although novel mutations

have been found in nearly all of the kindreds studied, a 4-

base deletion in exon 7 has been detected in multiple

families [64±66] and an unusual missense mutation in

exon 13 (A366S) has been identi®ed in two unrelated

young boys [67], suggesting that these two regions may

be genetic ``hot spots.''

These studies con®rm the molecular defect in AHO,

but they do not explain the striking variability in

biochemical and clinical phenotype. Why do some

Gas-coupled pathways show reduced hormone respon-

siveness (e.g., PTH, TSH, gonadotropins) whereas other

pathways are clinically unaffected (ACTH in the adrenal

and vasopressin in the renal medulla). One possible

interpretation of variable hormonal responsiveness is that

haploinsuf®ciency of Gas is tissue-speci®c; that is, in

some tissues a 50% reduction in Gas is still suf®cient to

Fig. 4. Mutations in the GNAS1 gene. The upper panel (A) depictsthe human GNAS1 gene, which spans over 20-kilobase pairs andcontains at least 13 exons and 12 introns. Unique mutations thatresult in loss of Gas function are depicted; missense mutations aredenoted by the symbol *. The lower panel (B) indicates the positionof missense mutations above the protein structure. Twopolymorphisms are denoted by the symbol � , and the position of theunchanged amino acid is denoted beneath the predicted Gsa protein( panel B). The site of two missense mutations that result in gain offunction (replacement of either Arg201 or Gln227) in patients withMcCune Albright syndrome or in sporadic tumors are depicted initalics.

270 Levine

facilitate normal signal transduction. However, this

explanation leaves unanswered the even more intriguing

paradox of why some subjects with Gas de®ciency have

hormone resistance (PHP type Ia) whereas others

have apparently normal hormone responsiveness

( pseudoPHP). Analysis of published pedigrees has

indicated that in most cases maternal transmission of

Gas de®ciency leads to PHP type Ia whereas paternal

transmission of the defect leads to pseudoPHP [13,68±

70], ®ndings which have implicated genomic imprinting

of the GNAS1 gene as a possible regulatory mechanism

[69]. Recent studies have indeed con®rmed that the

GNAS1 gene is imprinted, but in a far more complex

manner than had been anticipated. Two upstream

promoters, each associated with a large coding exon,

lie 35±40 kb upstream of GNAS1 exon 1. These

promoters are only 11 kb apart, yet show opposite

patterns of allele-speci®c methylation and monoallelic

transcription. The more 50 of these exons encodes

NESP55, which is expressed exclusively from the

maternal allele. By contrast, the XLas exon is paternally

expressed [53,54]. Despite the simultaneous imprinting

in both the paternal and maternal directions of the

GNAS1 gene, expression of Gas appears to be biallelic in

all human tissues examined [53,54,71]. The lack of

access to relevant tissues in patients with PHP type Ia has

hindered studies of Gas expression and stimulated

attempts to develop suitable animal models. Recently

two groups have succeeded in developing mice in which

one Gnas gene is disrupted, thereby generating murine

models of PHP type Ia [72,73] Although these mice have

reduced levels of Gas protein, they lack many of the

features of the human disorder. Biochemical analyses of

these heterozygous Gnas knockout mice suggest that Gsaexpression may derive from only the maternal allele in

some tissues (e.g., renal cortex) and from both alleles in

other tissues (e.g., renal medulla). Accordingly, mice that

inherit the defective Gnas gene maternally express only

that allele in imprinted tissues, such as the PTH-sensitive

renal proximal tubule, in which there is no functional

Gas protein. By contrast, the 50% reduction in Gas

expression that occurs in non-imprinted tissues, which

express both Gnas alleles, may account for more variable

and moderate hormone resistance in these sites (e.g., the

thyroid). Con®rmation of this proposed mechanism in

patients with AHO will require demonstration that the

human Gas transcript is paternally imprinted in the renal

cortex.

PHP type Ib

Subjects with PHP type Ib lack features of AHO,

manifest hormone resistance that is limited to PTH

target organs, and have normal Gas activity [40].

Although patients with PHP type Ib fail to show a

nephrogenous cAMP response to PTH, they often

manifest osteopenia or skeletal lesions similar to those

that occur in patients with hyperparathyroidism,

including osteitis ®brosa cystica [74]. Cultured bone

cells from one patient with PHP type Ib and osteitis

®brosa cystica were shown to have normal adenylyl

cyclase responsiveness to PTH in vitro [15]. These

observations have suggested that at least one intracellular

signaling pathway coupled to the PTH receptor may be

intact in patients with PHP type Ib.

Speci®c resistance of target tissues to PTH, and

normal activity of Gas, had implicated decreased

expression or function of the PTH1R as the cause for

hormone resistance. However, molecular studies have

failed to disclose mutations in the coding exons [75] and

promoter regions [76] of the PTH1R gene or its mRNA

[77]. Further evidence against a role for the PTH1R in the

pathogenesis of PHP type Ib comes from recent studies

showing that mice [78] and humans [79] with inactiva-

tion of one PTH1R gene allele do not manifest PTH

resistance or hypocalcemia. Moreover, loss of both

PTH1R genes results in Blomstrand chondrodysplasia, a

lethal genetic disorder characterized by advanced

endochondral bone maturation [79]. Thus, it is likely

that the molecular defect in PHP type Ib resides in other

gene(s) that regulate expression or activity of the PTH/

PTHrP receptor.

Although most cases of PHP type Ib appear to be

sporadic, familial cases have been described in which

transmission of the defect is most consistent with an

autosomal dominant pattern [80,81]. Recent studies have

used gene mapping to identify the molecular defect in

PHP type Ib [82]. In one study the unknown gene was

mapped to a small region of chromosome 20q13.3 near

the GNAS1 gene, thus raising the possibility that some

patients with PHP type Ib have inherited a defective

promoter or enhancer that regulates expression of Gas in

the kidney [82].

Pseudohypoparathyroidism type Ic

Resistance to multiple hormones has been described in

several patients with AHO who have do not have a

demonstrable defect in Gs or Gi [39,40,83]. This disorder

is termed PHP type 1c. The nature of the lesion in such

patients is unclear, but it could be related to some other

general component of the receptor-adenylyl cyclase

system, such as the catalytic unit [84]. Alternatively,

these patients could have functional defects of Gs (or Gi)

that do not become apparent in the assays presently

available.

Pseudohypoparathyroidism 271

Pseudohypoparathyroidism type II

PHP type II is the least common form of PHP. This

variant of PHP is typically a sporadic disorder, although

one case of familial PHP type II has been reported [85].

Patients do not have features of AHO. Renal resistance to

PTH in PHP type II patients is manifested by a reduced

phosphaturic response to administration of PTH, despite

a normal increase in urinary cAMP excretion [12]. These

observations suggest that the PTH receptor-adenylyl

cyclase complex functions normally to increase cyclic

AMP in patients with PHP type II. It is conceivable that

PTH resistance arises from an inability of intracellular

cAMP to initiate the chain of metabolic events that result

in the ultimate expression of PTH action.

In some patients with PHP type II the phosphaturic

response to PTH has been restored to normal after serum

levels of calcium have been normalized by treatment

with calcium infusion or vitamin D [86]. These results

point to the importance of Ca2� as an intracellular second

messenger. Finally, a similar dissociation between the

effects of PTH on generation of cAMP and tubular

reabsorption of phosphate has been observed in patients

with profound hypocalcemia due to vitamin D de®ciency

[87], suggesting that some cases of PHP type II may in

fact represent vitamin D de®ciency.

Conclusions

Although PHP is an uncommon syndrome, study of these

unusual patients continues to provide us with novel and

important insights about signal transduction that enhance

our understanding of all endocrine diseases. The ability

to study the consequences and pathophysiology of Gas

de®ciency in newly created animal models of PHP type

Ia now affords us the opportunity to uncover the more

mysterious nuances of this human disorder. Continued

gene mapping studies will no doubt soon disclose the

basis for PHP type Ib, and may provide even greater

surprises. With time, and great patience, some of these

discoveries will advance our ability to care for subjects

with PHP and other disorders of hormone signaling, and

will bring our focus back from bench to bedside.

Acknowledgments

This work was supported in part by United States Public

Health Service Grants R01 DK34281 and R01 DK56178

from the NIDDK and grant RR00055 from NCRR to the

Johns Hopkins General Clinical Research Center.

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