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Genetics
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Mutations Point mutation Frameshift mutation
Missense mutation Nonsense mutation Frameshift mutation Trinucleotide repeat mutation
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Mutations: Decreased gene product or inactive protein:
Enzymes:AR Regulation of complex metabolic pathways: e.g., LDL receptor Key structural proteins: dominant negative Gain of function: Almost always AD, e.g., Huntington disease
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Mendelian Disorders Expressed mutations in single genes of large effect Gene expression Dominant Recessive Codominant Pleiotropism vs genetic heterogeneity
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Autosomal Dominant Disorders
Onset: older age Reduced penetrance Variable expressivity New mutation: Frequency depends on reproductive capability In egg or sperm Germ cells of older fathers No increased risk in siblings
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Examples of AD inheritance
Huntington disease Neurofibromatosis Tuberous sclerosis Polycystic kidney disease Familial polyposis coli Hereditary spherocytosis Marfan syndrome Familial hypercholestrolemia
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Autosomal Recessive Disorders
The largest group in Mendelian disorders Almost all of the inborn errors of metabolism Enzymes Complete penetrance More uniform expression Early onset New mutations: ?
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Examples of AR inheritance
Cystic fibrosis PKU Lysosomal storage disease Sickle cell anemia Congenital adrenal hyperplasia Ehler-Danlos syndrome Spinal muscular atrophy
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X- Linked Disorders No Y- linked inheritance Almost all recessive
Males are hemizygote for X-linked mutant genes Random inactivation of one of the X- chromosomes; partial symptoms,e.g., G6PD
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Examples of XLR inheritance
Duchenne muscular dystrophy Hemophilia A and B G6PD deficiency Wiskott-Aldrich syndrome Diabetes insipidus Fragile X syndrome
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X- Linked Disorders Rare X-linked Dominant How is the inheritance?
Such as Vitamin D resistant rickets
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Mendelian Disorders Biochemical & Molecular Basis
Enzyme defects Defects receptors & transport systems Alterations in structure, function or quantity of nonenzyme proteins Genetically determined adverse reaction to drugs
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Enzyme Defects Enzyme: Decreased product.
Quantity. Quality. Decreased product. Albinism. Increased substrate or intermediates. PKU. Ipmaired inactivation of toxic substrate. Alpha1 Antitrypsin D.
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Genetically Determined Adverse Reaction to Drugs
Pharmacogenetics Enzyme deficiency unmasked by drug administration G6PD and Primaquine
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Disorders Associated With Defects in Structural Protein
Fibrillin: Marfan syndrome Collagen: Ehler Danlos syndrome Dystrophin: Duchene/Becker Spectrin/Ankyrin/Protein 4,1: Spherocytosis
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Marfan Syndrome Definition: Prevalence: 1/10,000 – 1/20,000
Connective tissue (elastic fiber) disorder Major involved organs Skeleton Eye Cardiovascular system Prevalence: 1/10,000 – 1/20,000
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Marfan Syndrome Autosomal dominant inheritance
70-80% familial vs 20-30% new mutations Variable expression: genetically heterogeneous Mutation Almost all Negative dominant Chromosome 15q21.1 FNB1 gene
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Elastic fibers Central core Peripheral microfibrillary network
Predominantly ellastin Peripheral microfibrillary network Predominantly fibrillin
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Fibrillin Particularly abundant in Aorta Ligaments
Ciliary zonules of lens
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Marfan Syndrome Pathogenesis
Inherited defect in fibrillin, an extracellular glycoprotein FBN1 gene mutation 70 different mutation Mostly nonsense mutations
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Marfan Syndrome Skeletal abnormalities Most striking Usually tall
Upper segment/lower segment: low Long extremities Pectus excavatum Long tapering fingers and toes
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Marfan Syndrome …Skeletal Abnormalities
Hyperflexibility of joints Scoliosis Kyphosis Rotation or slipping of thoracic vertebrae Dolichocephalic (long-headed) Cranial index less than 75% Cranial endex: width of skull/length of skull Bossing of frontal & supraorbital ridges
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Marfan Syndrome Ocular Changes
Characteristic Very rare in those without this disease Bilateral subluxation or dislocation of lens Ectopia lentis
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Marfan Syndrome Cardiovascular Changes
Aortic neurysm Cystic medionecrosis Intimal tear Dissection Towards root of aorta or iliac Ruptured dissection: cause of 30-45% of deaths Aortic regurgitation
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Marfan Syndrome ...Cardiovascular Changes
Mitral prolapse Loss of connective tissue support More common Less serious Floppy valve Elongated chordae tendineae Similar changes in tricuspid and rarely aorta
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Marfan Syndrome Diagnosis Presymptomatic Dx: RFLP
70 different mutations Direct gene diagnosis impossible
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Marfan Syndrome
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Marfan Syndrome
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Marfan Syndrome
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Defects in Collagen Synthesis or Structure
Osteogenesis imperfecta Alport syndrome Epidermolysis bullosa Ehler Danlos syndrome (EDS)
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Collagen Most abundant protein in animal world
At least 14 distinct collagen types General formula (gly-x-y)n Triple helix Three a chains: about 30 a chains
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Collagen Synthesis
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Ehler Danlos Syndrome (EDS)
Genetically heterogeneous At least 10 variant Clinical manifestations Skin Hyperextensible Extremely fragile Joints Prone to dislocation Hypermobile
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Ehler Danlos Syndrome (EDS)
Type VI Most commom AR form of EDS Mutation in lysyl hydroxylase gene Only collagen I and III Ocular fragility with rupture of cornea and retinal detachment
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Ehler Danlos Syndrome (EDS)
Type IV AD inheritance Collagen type III At least 3 different mutation: Abnormal collagen Decreased synthesis Decreased excretion Some negative dominant Rupture of colon and large arteries
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Ehler Danlos Syndrome (EDS)
Type VII AD inheritance Abnormal procollagen type I Peptidase can not cleave the N terminal Genes a1[I] a2[I]
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Ehler Danlos Syndrome (EDS)
Type IX XLR inheritance Mutation in copper binding protein Decreased activity of lysyl hydroxylase Cross-linking of collagen & elastic High level of copper within the cell Low serum copper & ceruloplasmin levels
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Ehler Danlos Syndrome (EDS)
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Ehler Danlos Syndrome (EDS)
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Familial Hypercholestrolemia
A receptor disease The most frequent mendelial disorder 3-6% of survivors of MI Mutation in the gene encoding LDL receptor Hypercholestrolemia Premature atherosclerosis: MI Xanthoma
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Familial Hypercholestrolemia
Heterozygotes 1/500 2-3 times higher plasma cholestrol Homozygotes 5-6 times higher plasma cholestrol MI before 20 years of age
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Familial Hypercholestrolemia
Pathogenesis Decreased LDL clearance (uptake) Increased LDL production More IDL coverts to LDL In both heterozygotes and homozygotes Increased LDL uptake by macrophage/monocyte (scavenger receptor) Acetylated or oxidized LDL
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Familial Hypercholestrolemia
LDL receptor gene Extremely large 18 exons 5 domains 45 kb
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Familial Hypercholestrolemia
LDL receptor gene More than 150 different mutations Insertion Deletion Missense Nonsense Mutations categorized in 5 groups
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Management Statins Gene therapy HMG-CoA reductase inhibition
Decreased synthesis of cholestrol Increased synthesis of LDL receptor Gene therapy
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Lysosomal Storage Diseases
Definition Lack of any protein essential for the normal function of lysosomes
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Lysosomal Storage Diseases
Involved organs depend on The site where most of the material to be degraded is found. GM1 & GM2 gangliosidoses Brain Mucopolysaccharidoses All of the body The location where most of the degradation normally occurs Mononuclear phagocytes
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Lysosomal Storage Diseases
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Tay-Sachs Disease Most common form of GM2 gangliosidoses
Ashkenazi jews 1/30 carrier rate All tissues lack hexosaminidase A Including leukocytes and plasma GM2 accumulation in many organs Heart, liver, spleen,CNS, autonomous nervous system, retina, ..
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Niemann-Pick Disease Rare lysosomal storage disease
Lysosomal accumulation of sphingomyelin Sphingomyelinase deficiency Common in Ashkenazi jews Types A & B Previously type C Defect in intracellular cholestrol esterification & transport
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Sphingomyelin Present in cell membranes
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Niemann-Pick Disease Type A Severe infantile type 75-80% of cases
Extensive neurologic involvement Severe visceral accumulation of sphingomyelin 75-80% of cases Survival: less than 3 years
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Niemann-Pick Disease …Type A Missense mutation
Complete deficiency of sphingomyelinase
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Niemann-Pick Disease Type B Organomegaly No CNS involvement
Survive adulthood
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Niemann-Pick Disease Diagnosis
Biochemical studies Sphingomyelinase activity in leukocytes and cultured fibroblasts DNA probes: Both patients and carriers
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Niemann-Pick Disease
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Gaucher Disease Glucocerebrosidase gene mutation
Accumulation of glucocerebroside in phagocytes and sometimes CNS
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Gaucher Disease Most common lysosomal storage disease Types
I (chronic non-neuropathic): 99% Decreased enzyme activity Without CNS involvement Predominantly spleen & skeleton Pancytopenia or thrombocytopenia Pathologic Fx and bone pain Progressive but compatible with long life European Jews
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Gaucher Disease …types II (acute neuropathic) No enzyme activity
No predilection for jews Infantile Progressive involvement of CNS & early death Hepatosplenomegaly
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Gaucher Disease
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Gaucher Disease Diagnosis Homozygotes Heterozygotes Enzyme activity
Peripheral blood leukocytes Cultured skin fibroblasts Heterozygotes Enzymatic methods not reliable Detection of mutation More than 30 different mutations
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Gaucher Disease Management Difficult Replacement therapy
Recombinant enzyme: extremely expensive Bone marrow transplantation Gene therapy: future
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Glycogen Storage Diseases
AKA: Glycogenoses Genetic disease with metabolic defect in synthesis or catabolism of glycogen
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Glycogen Storage Diseases
Hepatic type Hepatomegaly Hypoglycemia Examples Von Gierke: Glucose-6-phosphatase (I) Liver phosphorylase (VI) Debranching enzyme(III)
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Glycogen Storage Diseases
Myopathic type Muscle weakness Cramps following exercise Following exercise lactate does not increase Examples McArdle: muscle phosphorylase(V) Muscle phosphofructokinase (VII)
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Glycogen Storage Diseases
Miscellaneous Pompe (acid maltase, a-glucosidase) Lysosomal accumulation of glycogen Predominantly heart involvement Early death
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Pompe Disease
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Disorders With multifactorial Inheritance
Some normal phenotypes Height Intelligence Eye & hair color
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Normal Distribution Height x X _ -2.58x -1.65x
90% Samples 95% Samples 99% Samples Height 33
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Disorders With multifactorial Inheritance
Different diseases Cleft lip & palate Congenital heart disease Coronary heart disease HTN Gout DM Pyloric stenosis
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Disorders With multifactorial Inheritance
Both environment and two or more mutant genes (dosage effect) Not polygenic inheritance Variable expressibility Reduced penetrance First rule out mendelian & chromosomal inheritance
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Disorders With multifactorial Inheritance
Risk of expression: # of mutant genes inherited Severity of disease # of diseased individuals The rate of recurrence of the disorder (in range of 2-7%) is the same for all first-degree relatives of affected individuals Identical twins: concordance 20-40% Expression of multifactorial trait Continuous: height Discontinuous: DM
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