PowerPoint Presentation: MUTATION and GENETIC Disease M.Prasad Naidu MSc Medical Biochemistry, Ph.D,.
PowerPoint Presentation: mutation effect on protein function phenotypic expression classes of genetic disease
PowerPoint Presentation: Mutations result in different alleles alleles are classified as “dominant” or “recessive” dominant phenotypes – observable in heterozygotes recessive phenotypes – observable only in homozygotes
PowerPoint Presentation: 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
PowerPoint Presentation: complementation as in XP, profound hearing loss penetrance (100% - achondroplasia - unusual ) variable expression Variations in phenotypic manifestation of mutant alleles are due to:
PowerPoint Presentation: 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:
PowerPoint Presentation: 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.
PowerPoint Presentation: 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.):
PowerPoint Presentation: 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)
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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.
PowerPoint Presentation: 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)
PowerPoint Presentation: 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)
PowerPoint Presentation: 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)
PowerPoint Presentation: CYTOGENETICS
PowerPoint Presentation: Common chromosome structural disorders Chromosome banding Aneuploidies: nondisjunction Chromosome breakage syndromes; translocation Faulty DNA metabolism chromosome syndromes Genomic imprinting; UDP Sex reversal
PowerPoint Presentation: Banding
PowerPoint Presentation: Banding
PowerPoint Presentation: Sister chromatid exchanges in Bloom syndrome
PowerPoint Presentation: Banding (FISH)
PowerPoint Presentation: Aneuploidy: Nondisjunction
PowerPoint Presentation: The phenotypes associated with sex chromosome trisomies are less severe than those associated with autosomal trisomies.
PowerPoint Presentation: Clinical phenotype of Turner syndrome is due to haploinsufficiency.
PowerPoint Presentation: Structural chromosome abnormalities arising from chromosome breakage : Deletions Ring chromosomes Isochromosomes Translocation
PowerPoint Presentation: Cri du chat, 5p- Deletions
PowerPoint Presentation: Ring Chromosomes ; Isochromosomes
PowerPoint Presentation: Translocation examples and consequences
PowerPoint Presentation: Translocation Reciprocal translocation Robertsonian translocation
PowerPoint Presentation: 46,XY,t(11;16)(q24;q23)
PowerPoint Presentation: Translocation PAIRING AT MEIOSIS
PowerPoint Presentation: Translocation: non-random X-inactivation
PowerPoint Presentation: Structural chromosomal abnormalities arising from faulty DNA metabolism : Slipped mispairing during DNA replication Nonreciprocal recombination
PowerPoint Presentation: Slipped mispairing during DNA replication
PowerPoint Presentation: N = normal P = unmethylated premutation MN/P = methylated normal or premutation F = methylated full mutation Ecl XI: methylation sensitive MN/P
PowerPoint Presentation: Non-reciprocal recombination
PowerPoint Presentation: Non-reciprocal recombination
PowerPoint Presentation: Genomic Imprinting : mechanism distribution consequences
PowerPoint Presentation: Map of Imprinted Regions in Human Genome Maternally inherited homolog (left) Paternally inherited homolog (right)
PowerPoint Presentation: gene A
PowerPoint Presentation: Genomic Imprinting
PowerPoint Presentation: Sex Reversal : Role of the sry gene
PowerPoint Presentation: Sex reversal due to translocation of SRY from Y to X
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