1 / 31

Medical Genetics-Biochemical Genetics Robert F. Waters, PhD

Medical Genetics-Biochemical Genetics Robert F. Waters, PhD. One gene-One enzyme Many proteins are different but do not cause clinical problems Polymorphism (multiple structures) Multiple “normal” forms Caused by mutations Different types of proteins..not just enzymes. Main Categories.

pascha
Download Presentation

Medical Genetics-Biochemical Genetics Robert F. Waters, PhD

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Medical Genetics-Biochemical GeneticsRobert F. Waters, PhD • One gene-One enzyme • Many proteins are different but do not cause clinical problems • Polymorphism (multiple structures) • Multiple “normal” forms • Caused by mutations • Different types of proteins..not just enzymes

  2. Main Categories • The Hemoglobins • Inborn Errors of Metabolism • Genetic response to drugs • Pharmacogenetics

  3. The Hemoglobins • Defects in hemoglobin synthesis • Hemoglobinopathies • One of the first was Sickle Cell Anemia • Neel (1949) • Pauling, et. al. (1949) • Sickle Cell Anemia is essentially a “molecular disease”

  4. Structure of Hemoglobin • Two main parts • Globin (Polypeptide Chains) • Two alpha and two beta • Heme (Porphyrin) • Iron containing portion • Oxygen binding

  5. Normal Hemoglobin • Adult hemoglobin (HbA) • MW. Approx. 68000 • Structural formula • 22 • Alpha chains have 141 AAs • Beta chains 146 AAs • Alpha and beta chains are very similar in primary and tertiary structure

  6. Myoglobin is Different • Oxygen carrying molecule of muscles • Single polypeptide chain

  7. Different Gene Loci for Globin Part of Hb •      • Alpha, beta, gamma, delta, epsilon • Five different structural gene loci • HbF (Fetal Hemoglobin) • Formed in uterus • Disappears after birth • 2 2 • Two different types of HbF differing by only one amino acid…glycine • HbA2 • 2% of adult variant • 2 2 • Two types of embryonic hemoglobin • First 90 days • Gower I (4) and Gower II (22)

  8. Abnormal Hemoglobin • HbS (Sickle Cell - 6:glu val) • HbC (-6:glulys) • Hb Hopkins-2 (- 112:hisasp) • HbC Georgetown (- 6:glu val+) • + means another substitution as well • Hb Freiburg (-23 deletion)

  9. Sickle Cell Disease • Severe hemolytic anemia • Anemia • Jaundice • Vascular obstruction (Sickle cells) • Painful infarcts • High incidence in equatorial Africa • Separated originally by electrophoresis • Pauling, Sanger, Wells (1949) • Mixture of normal and abnormal (heterozygous)

  10. Hereditary Persistence of HbF • Rare • Sub-clinical • Gene to turn on HbA formation is blocked

  11. Thalassemias • Beta gene turned on just before birth • Alpha gene throughout gestation • Derived from Greek word for sea—thalassa • Due to low production of alpha or beta chains NOT amino acid substitution

  12. Alpha Thalassemia • Usually high expressivity • Lethal • Associated with operator gene malfunction

  13. Beta Thalassemia • Mediterranean Anemia • Wide expressivity • May be expressed neonatally • Differential diagnosis • Different from iron-deficiency anemia

  14. Inborn Errors of Metabolism • Enzymatic defect (structure) • Enzyme substrate problem • Enzyme co-enzyme malfunction • Enzyme co-factor (metal) malfunction • Build up before—feed after • Usually autosomal recessive • Otherwise would probably be lethal • Some are hemizygous (XY)

  15. Consequences-Overview • Accumulation of a precursor • Accumulated precursor may be toxic • E.g., pyruvate • Alternate minor pathways may start producing other toxic metabolites • E.g., PKU • Deficiency of product • Product may be precursor to other substance. • E.g., tyrosine and thyronines • Feedback inhibition may be impaired due to lack of product • Causes lack of feedback inhibition

  16. Partial Listing of Lesions • Glycolytic Pathway • PDH Complex • Albinism (Two Types) • Cystinuria • Increased secretion of cystine, lysine, arginine, ornithine • Aminoaciduria • AR (variable expressivity) • Renal failure

  17. Partial Listing of Lesions:Cont • Galactosemia • Galactose-1-phosphate uridyltransferase • AR • Hepatosplenomegaly • Mental retardation • Note: Galactokinase deficiency

  18. Partial Listing of Lesions:Cont • G6PD Deficiency • Many Variants • Hemolytic anemia • XR • Oxidative stress • Sickle Cell Anemia

  19. Partial Listing of Lesions:Cont • Glycogen storage diseases • Type I (von Gierke’s) • Hepatomegaly, mental retardation, hypoglycemia • Glucose-6-phosphatase • Type VIII (Glycogen Storage Disease) • Hepatomegaly,mild acidosis, hypoglycemia • XR • Phorphorylase kinase

  20. Partial Listing of Lesions:Cont • Tay-Sachs Disease • Onset at 4 to 6 months • Death 2 to 4 years • AR • Degenerative neurological changes • Gangliosidosis • Reduced hexosaminidase

  21. Partial Listing of Lesions:Cont • Hartnup Disease • Tryptophan transport • Neurological change • AR • Hemoglobinopathies (See Earlier) • Thalassemias

  22. Partial Listing of Lesions:Cont • Homocystinuria • Dislocated lenses • AR • Accumulation of methionine and homocystine

  23. Partial Listing of Lesions:Cont • Lesch-Nyhan Syndrome • Uric Aciduria • Self-mutilation • Mental retardation • Cerebral palsy • Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) • XR

  24. Partial Listing of Lesions:Cont • Mucopolysaccharidoses I • Hurler’s Syndrome • “Gargoyle” Appearance • Mental retardation • Corneal clouding • Cardiovascular degeneration • Dwarfism • Mucopolysaccharide accumulation

  25. Partial Listing of Lesions:Cont • Mucopolysaccharidoses II • Hunter’s Syndrome • Less severe than Hurler’s • No evidence of corneal clouding • Orotic aciduria • Urinary excretion of orotic acid • Precursor to pyrimidine nucleotides • Pentosuria • AR • “False Diabetes”

  26. Partial Listing of Lesions:Cont • PKU • Porphyria (Acute Intermittent) • Abdominal pain • Neurological problems • Excessive excretion of -amino levulinic acid (ALA) • Excessive hepatic ALA synthetase • AR

  27. Partial Listing of Lesions:Cont • Congenital Spherocytosis • Episodes of hemolytic anemia • Defect in RBC membrane • AD • Patients are heterozygous

  28. Partial Listing of Lesions:Cont • Tyrosinemia • Acute liver disease • AR • Tyrosine transaminase • Wilson’s Disease • Cirrhosis of liver • Neurological damage • Improper copper metabolism • AR • Build up of stored copper • Decreased serum levels of ceruloplasmin • Treatment by Penicillamine removes stored Cu

  29. Partial Listing of Lesions:Cont • Maple Syrup Urine Disease • BCAA dehydrogenase • Alcaptonuria • Dark Urine Disease • Other Metabolic Pathways • Vitamin Pathways • E.g., holoenzyme carboxylase • Pyruvate carboxylase and biotin

  30. Pharmacogenetics • Drug reactions and interactions associated with genetics • Genetic Profiling • Genetic Probes

  31. Genetic Polymorphisms • Different phenotypes • G6PD Variants (Example) • BA • A- • BA- • B- • B • A

More Related