basic medical genetics concepts. mutation effect on protein function phenotypic expression ...
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BASIC MEDICAL BASIC MEDICAL GENETICS GENETICS CONCEPTSCONCEPTS
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mutation effect on protein function
phenotypic expression
classes of genetic disease
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Mutations result in different alleles
• alleles are classified as “dominant” or “recessive”
• dominant phenotypes – observable in heterozygotes
• recessive phenotypes – observable only in homozygotes
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• loss-of-function (most common) e.g. Decreased amount normal protein: Inborn errors of metabolism as in Tay-Sachs [recessive] Haploinsufficiency as in FH [dominant]
• gain-of-function e.g. Gene dosage effects as in trisomy 21 [dominant]; Dominant-negative effect as in OI [dominant] Abnormal protein properties as in HD [dominant]
• novel property e.g. HbS [recessive]
• inappropriate expression e.g. Oncogenes in cancer
Mutations are classified by effect on protein function
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• complementation as in XP, profound hearing loss
• penetrance (100% - achondroplasia - unusual)
• variable expression
Variations in phenotypic manifestation of mutant alleles are due to:
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• allelic heterogeneity: hemophilia variants
• locus heterogeneity: hyperphenylalanemias
• modifier loci: Waardenburg syndrome (methylation); Alzheimer’s (multiple genes); SNPs
• environment (XP, α-1 antitrypsin deficiency)
Causes of variable expression:
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Common classes of genetic disease:
1. enzyme defects (PKU; Lesch-Nyhan; Tay-Sachs; I-cell disease; XP)
• Almost always recessive.
• Pathophysiology due to substrate accumulation,product deficiency, or both.
• When substrate is diffusible, the pathophysiology is unpredictable; when substrate can’t diffuse, the cell in which it accumulates is damaged.
• Several enzyme functions can be affected.
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2. Defects in receptor proteins (Familial hypercholesterolemia)
3. Transport defects (Cystic fibrosis)
4. Disorders of structural proteins (Duchenne muscular dystrophy; Osteogenesis imperfecta)
5. Neurodegenerative disorders (Alzheimer’s disease; triplet repeat disorders)
6. Mitochondrial diseases (MELAS, MERRF)
7. Pharmacogenetic diseases (malignant hyperthermia; G6DP)
Common classes of genetic disease (cont.):
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Triplet Repeat Disorders
• Dynamic expansion of DNA triplet repeats
• Normal alleles polymorphic
• Inheritance dominant or recessive
• Presymptomatic, symptomatic expansion size varies
• Base sequence, location of repeat varies
• Parent-of-origin effects on repeat expansion varies (anticipation)
• Stability during meiosis and mitosis varies (variable expression)
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• Huntington Disease (autosomal dominant)
• Spinobulbar muscular atrophy (X-linked recessive; androgen receptor)
• CAG repeat
• Anticipation: expansion occurs preferentially during male gametogenesis
• Variable expression: mitotic instability low (limited
mosaicism)
• Protein aggregation, not loss-of-function
Polyglutamine disorders
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Fragile X Syndrome
• X-linked recessive
• CGG repeat in 5’ untranslated region of FRA gene (posttranscriptional regulator; methylation effects)
• Most common form of hereditary mental retardation
• Anticipation: expansion occurs preferentially in female gametogenesis
• Variable expression: Mitotic instability high
• Disease caused by loss of function; very large expansions needed
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Myotonic Dystrophy
• Autosomal dominant
• CTG repeat in 3’ untranslated region of protein kinase gene; mechanism of pathophysiology unknown.
• Anticipation: either parent can transmit amplified copy; massive expansion occurs only in maternal gametogenesis
• Variable expression: mitotic instability high
• Abnormal transcript processing, not deletions, point mutations, etc.
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Freidreich ataxia
• Autosomal recessive
• GAA repeat in intron of mitochondrial gene frataxin (involved in iron metabolism).
• Anticipation: no parent of origin effects
• Variable expression: mitotic instability low
• Loss of function
• 4% are compound heterozygotes (expansion/point mutation)
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Mitochondrial Disorders3 types of mutations
• missense mutations in coding regions of genes that alter activity of OXPHOS proteins (Leigh disease-ATPase)
• point mutations in tRNA or rRNA genes that impair mitochondrial protein synthesis (MELAS; MERRF)
• rearrangements that generate deletions/duplications in mtDNA ( not usually transmitted from affected mother to offspring; disorders occur as sporadic new cases-Kearns-Sayre syndrome)
Maternal inheritance
Usually heteroplasmic (phenotypic expression: reduced penetrance, variable expression, pleiotropy)
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Pharmacogenetic Diseases• Unanticipated reactions to medications largely/entirely genetic (6.7% incidence in American hospitals; 0.3% fatal).
• Single gene defects or multifactorial
Examples:
• Malignant hyperthermia (autosomal dominant-Ca+ release channel; other loci)
• Acute Intermittent Porphyria (autosomal dominant disease: drug-related alteration in gene expression of heme biosynthetic enzyme)
• G6PD (X-linked recessive; more than 400 variants; most common disease-producing single gene enzyme defect of humans)
• Acetylation polymorphism (slow or rapid drug inactivation)
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PRINCIPLES OF PRINCIPLES OF CLINICAL CLINICAL
CYTOGENETICSCYTOGENETICS
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Common chromosome structural disorders
Chromosome banding
Aneuploidies: nondisjunction
Chromosome breakage syndromes; translocation
Faulty DNA metabolism chromosome syndromes
Genomic imprinting; UDP
Sex reversal
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Banding
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Banding
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Sister chromatid exchanges in Bloom syndrome
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Banding (FISH)
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Aneuploidy: Nondisjunction
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The phenotypes associated with sex chromosome trisomies are less severe than those associated with autosomal trisomies.
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Clinical phenotype of Turner syndrome is due to haploinsufficiency.
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Structural chromosome abnormalities arising from chromosome breakage:
• Deletions
• Ring chromosomes
• Isochromosomes
• Translocation
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Cri du chat, 5p-
Deletions
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Ring Chromosomes; Isochromosomes
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Translocation
examples and consequences
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Translocation
Reciprocal translocation
Robertsonian translocation
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46,XY,t(11;16)(q24;q23)
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Translocation
PAIRING AT MEIOSIS
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Translocation: non-random X-inactivation
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Structural chromosomal abnormalities arising from faulty DNA metabolism:
• Slipped mispairing during DNA replication
• Nonreciprocal recombination
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Slipped mispairing during DNA replication
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N = normal
P = unmethylated premutation
MN/P = methylated normal or premutation
F = methylated full mutation
EclXI: methylation sensitive
MN/P
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Non-reciprocal recombination
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Non-reciprocal recombination
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Genomic Imprinting:
• mechanism
• distribution
• consequences
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Map of Imprinted Regions in Human
Genome
Maternally inherited homolog (left)
Paternally inherited homolog (right)
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gene A
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Genomic Imprinting
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Sex Reversal: Role of the sry gene
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Sex reversal due to translocation of SRY from Y to X