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