mutation & Genetic Disease

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Biochemistry

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MUTATION and GENETIC Disease M.Prasad Naidu MSc Medical Biochemistry, Ph.D,.

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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: 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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Defects in receptor proteins ( Familial hypercholesterolemia ) Transport defects ( Cystic fibrosis ) Disorders of structural proteins ( Duchenne muscular dystrophy; Osteogenesis imperfecta ) Neurodegenerative disorders ( Alzheimer’s disease ; triplet repeat disorders) Mitochondrial diseases ( MELAS, MERRF ) Pharmacogenetic diseases ( malignant hyperthermia; G6DP ) Common classes of genetic disease (cont.):

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Triplet Repeat Disorders D ynamic 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 Disorders 3 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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CYTOGENETICS

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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 Ecl XI: 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

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