Genetics

1. Genetics

2. Mutations Point mutation Missense mutation Nonsense mutation Frameshift mutation Trinucleotide repeat mutation

3. 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

4. Mendelian Disorders Expressed mutations in single genes of large effect Gene expression Dominant Recessive Codominant Pleiotropism vs genetic heterogeneity

5. 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

6. Examples of AD inheritance Huntington disease Neurofibromatosis Tuberous sclerosis Polycystic kidney disease Familial polyposis coli Hereditary spherocytosis Marfan syndrome Familial hypercholestrolemia

7. 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: ?

8. Examples of AR inheritance Cystic fibrosis PKU Lysosomal storage disease Sickle cell anemia Congenital adrenal hyperplasia Ehler-Danlos syndrome Spinal muscular atrophy

9. 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

10. Examples of XLR inheritance Duchenne muscular dystrophy Hemophilia A and B G6PD deficiency Wiskott-Aldrich syndrome Diabetes insipidus Fragile X syndrome

11. X- Linked Disorders Rare X-linked Dominant How is the inheritance? Such as Vitamin D resistant rickets

12. Mendelian DisordersBiochemical & Molecular Basis Enzyme defects Defects receptors & transport systems Alterations in structure, function or quantity of nonenzyme proteins Genetically determined adverse reaction to drugs

13. Enzyme Defects Enzyme: Quantity. Quality. Decreased product. Albinism. Increased substrate or intermediates. PKU. Ipmaired inactivation of toxic substrate. Alpha1 Antitrypsin D.

14. Genetically Determined Adverse Reaction to Drugs Pharmacogenetics Enzyme deficiency unmasked by drug administration G6PD and Primaquine

15. Disorders Associated With Defects in Structural Protein Fibrillin: Marfan syndrome Collagen: Ehler Danlos syndrome Dystrophin: Duchene/Becker Spectrin/Ankyrin/Protein 4,1: Spherocytosis

16. Marfan Syndrome Definition: Connective tissue (elastic fiber) disorder Major involved organs Skeleton Eye Cardiovascular system Prevalence: 1/10,000 � 1/20,000

17. 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

19. Elastic fibers Central core Predominantly ellastin Peripheral microfibrillary network Predominantly fibrillin

20. Fibrillin Particularly abundant in Aorta Ligaments Ciliary zonules of lens

21. Marfan Syndrome Pathogenesis Inherited defect in fibrillin, an extracellular glycoprotein FBN1 gene mutation 70 different mutation Mostly nonsense mutations

22. Marfan Syndrome Skeletal abnormalities Most striking Usually tall Upper segment/lower segment: low Long extremities Pectus excavatum Long tapering fingers and toes

23. 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

24. Marfan SyndromeOcular Changes Characteristic Very rare in those without this disease Bilateral subluxation or dislocation of lens Ectopia lentis

25. Marfan SyndromeCardiovascular Changes Aortic neurysm Cystic medionecrosis Intimal tear Dissection Towards root of aorta or iliac Ruptured dissection: cause of 30-45% of deaths Aortic regurgitation

26. 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

27. Marfan Syndrome Diagnosis Presymptomatic Dx: RFLP 70 different mutations Direct gene diagnosis impossible

28. Marfan Syndrome

29. Marfan Syndrome

30. Marfan Syndrome

32. Defects in Collagen Synthesis or Structure Osteogenesis imperfecta Alport syndrome Epidermolysis bullosa Ehler Danlos syndrome (EDS)

33. 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

34. Collagen Synthesis

35. Ehler Danlos Syndrome (EDS) Genetically heterogeneous At least 10 variant Clinical manifestations Skin Hyperextensible Extremely fragile Joints Prone to dislocation Hypermobile

36. 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

37. 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

38. Ehler Danlos Syndrome (EDS) Type VII AD inheritance Abnormal procollagen type I Peptidase can not cleave the N terminal Genes a1[I] a2[I]

39. 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

40. Ehler Danlos Syndrome (EDS)

41. Ehler Danlos Syndrome (EDS)

42. 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

43. Familial Hypercholestrolemia Heterozygotes 1/500 2-3 times higher plasma cholestrol Homozygotes 5-6 times higher plasma cholestrol MI before 20 years of age

46. 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

47. Familial Hypercholestrolemia LDL receptor gene Extremely large 18 exons 5 domains 45 kb

48. Familial Hypercholestrolemia LDL receptor gene More than 150 different mutations Insertion Deletion Missense Nonsense Mutations categorized in 5 groups

50. Management Statins HMG-CoA reductase inhibition Decreased synthesis of cholestrol Increased synthesis of LDL receptor Gene therapy

51. Lysosomal Storage Diseases Definition Lack of any protein essential for the normal function of lysosomes

52. 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

53. Lysosomal Storage Diseases

56. 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, ..

61. 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

62. Sphingomyelin

63. Niemann-Pick Disease Type A Severe infantile type Extensive neurologic involvement Severe visceral accumulation of sphingomyelin 75-80% of cases Survival: less than 3 years

64. Niemann-Pick Disease �Type A Missense mutation Complete deficiency of sphingomyelinase

65. Niemann-Pick Disease Type B Organomegaly No CNS involvement Survive adulthood

66. Niemann-Pick DiseaseDiagnosis Biochemical studies Sphingomyelinase activity in leukocytes and cultured fibroblasts DNA probes: Both patients and carriers

67. Niemann-Pick Disease

68. Gaucher Disease Glucocerebrosidase gene mutation Accumulation of glucocerebroside in phagocytes and sometimes CNS

69. 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

70. Gaucher Disease �types II (acute neuropathic) No enzyme activity No predilection for jews Infantile Progressive involvement of CNS & early death Hepatosplenomegaly

77. Gaucher Disease Diagnosis Homozygotes Enzyme activity Peripheral blood leukocytes Cultured skin fibroblasts Heterozygotes Enzymatic methods not reliable Detection of mutation More than 30 different mutations

78. Gaucher Disease Management Difficult Replacement therapy Recombinant enzyme: extremely expensive Bone marrow transplantation Gene therapy: future

79. Glycogen Storage Diseases AKA: Glycogenoses Genetic disease with metabolic defect in synthesis or catabolism of glycogen

81. Glycogen Storage Diseases Hepatic type Hepatomegaly Hypoglycemia Examples Von Gierke: Glucose-6-phosphatase (I) Liver phosphorylase (VI) Debranching enzyme(III)

83. Glycogen Storage Diseases Myopathic type Muscle weakness Cramps following exercise Following exercise lactate does not increase Examples McArdle: muscle phosphorylase(V) Muscle phosphofructokinase (VII)

85. Glycogen Storage Diseases Miscellaneous Pompe (acid maltase, a-glucosidase) Lysosomal accumulation of glycogen Predominantly heart involvement Early death

86. Pompe Disease

87. Disorders With multifactorial Inheritance Some normal phenotypes Height Intelligence Eye & hair color

88. Normal Distribution

89. Disorders With multifactorial Inheritance Different diseases Cleft lip & palate Congenital heart disease Coronary heart disease HTN Gout DM Pyloric stenosis

90. 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

91. 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