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Medical Genetics-Biochemical Genetics Robert F. Waters, PhD One gene-One enzyme Many proteins are different but do not cause clinical problems Polymorphism.

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Presentation on theme: "Medical Genetics-Biochemical Genetics Robert F. Waters, PhD One gene-One enzyme Many proteins are different but do not cause clinical problems Polymorphism."— Presentation transcript:

1 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

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 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 HbA 2 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


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