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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 (multiple structures)
• Multiple “normal” forms• Caused by mutations
Different types of proteins..not just enzymes
Main Categories The Hemoglobins Inborn Errors of Metabolism Genetic response to drugs
Pharmacogenetics
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”
Structure of Hemoglobin Two main parts
Globin (Polypeptide Chains)• Two alpha and two beta
Heme (Porphyrin)• Iron containing portion
Oxygen binding
Normal Hemoglobin Adult hemoglobin (HbA)
MW. Approx. 68000 Structural formula
22
• Alpha chains have 141 AAs• Beta chains 146 AAs
• Alpha and beta chains are very similar in primary and tertiary structure
Myoglobin is Different Oxygen carrying molecule of
muscles Single polypeptide chain
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 (22)
Abnormal Hemoglobin HbS (Sickle Cell - 6:glu val) HbC (-6:glulys) Hb Hopkins-2 (- 112:hisasp) HbC Georgetown (- 6:glu val+)
+ means another substitution as well Hb Freiburg (-23 deletion)
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)
Hereditary Persistence of HbF
Rare Sub-clinical Gene to turn on HbA formation is
blocked
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
Alpha Thalassemia Usually high expressivity
Lethal Associated with operator gene
malfunction
Beta Thalassemia Mediterranean Anemia Wide expressivity May be expressed neonatally Differential diagnosis
Different from iron-deficiency anemia
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)
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
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
Partial Listing of Lesions:Cont
Galactosemia Galactose-1-phosphate
uridyltransferase AR Hepatosplenomegaly Mental retardation Note: Galactokinase deficiency
Partial Listing of Lesions:Cont
G6PD Deficiency Many Variants Hemolytic anemia XR Oxidative stress
Sickle Cell Anemia
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
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
Partial Listing of Lesions:Cont
Hartnup Disease Tryptophan transport Neurological change AR
Hemoglobinopathies (See Earlier) Thalassemias
Partial Listing of Lesions:Cont
Homocystinuria Dislocated lenses AR Accumulation of methionine and
homocystine
Partial Listing of Lesions:Cont
Lesch-Nyhan Syndrome Uric Aciduria Self-mutilation Mental retardation Cerebral palsy Hypoxanthine-guanine phosphoribosyl
transferase (HGPRT) XR
Partial Listing of Lesions:Cont
Mucopolysaccharidoses I Hurler’s Syndrome “Gargoyle” Appearance Mental retardation Corneal clouding Cardiovascular degeneration Dwarfism Mucopolysaccharide accumulation
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”
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
Partial Listing of Lesions:Cont
Congenital Spherocytosis Episodes of hemolytic anemia Defect in RBC membrane AD
• Patients are heterozygous
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
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
Pharmacogenetics Drug reactions and interactions
associated with genetics Genetic Profiling Genetic Probes
Genetic Polymorphisms Different phenotypes G6PD Variants (Example)
BA A- BA- B- B A
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