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Genetic Disorders (No 4)

Genetic Disorders (No 4)

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Genetic disorders 4 Genetic disorders 4 Presentation Transcript

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  • Genetic Disorders Biochemical and Molecular Basis of Single Gene (Mendelian) Disorders Dr. Shahab Riaz
  • Biochemical and Molecular Basis of Single Gene (Mendelian) Disorders
    • Protein or gene product synthesis affected by:
    • Affecting transcription
    • Affecting mRNA processing
    • Affecting translation
    • Phenotypic Effects of Altered Protein:
    • Direct influence by abnormal protein on structure
    • Indirect influence by interaction of abnormal with normal protein
    • Example:
    • Ehlers Danlos Syndrome (abnormal collagen)
    • Vascular Type EDS  mutation in one of the collagen genes
    • Kyphoscoliosis Type EDS  Collagen genes normal  mutant lysyl hydroxylase enzyme gene  abnormal collagen cross-linking
  • Biochemical and Molecular Basis of Single Gene (Mendelian) Disorders
    • Mechanisms:
    • Enzyme defects and their consequences
    • Defects in membrane receptors and transport systems
    • Alterations in the structure, function or quantity of non-enzyme proteins
    • Mutations resulting in unusual reactions to drugs
  • Biochemical and Molecular Basis of Single Gene (Mendelian) Disorders
    • Enzyme defects and their consequences:
    • Defective enzyme  reduced activity OR reduced amount
    • As a consequence  metabolic block
    • Accumulation of Substrate (galactosemia, phenylketonuria, LSD)
    • Metabolic block, end product (melanin lack, tyrosinase)
    • Failure to inactivate toxic substrate ( α 1-AT deficiency)
  • Biochemical and Molecular Basis of Single Gene (Mendelian) Disorders
    • Defects in membrane receptors and transport systems:
    • Active transport across CM  receptor mediated endocytosis OR Transport protein
    • E.g., Familial Hypercholesterolemia  LDL receptors  LDL accumulates outside cell  intermediary mechanisms  cholesterol
  • Biochemical and Molecular Basis of Single Gene (Mendelian) Disorders
    • Alterations in the structure, function or quantity of non-enzyme proteins:
    • Quality compromised  sickle cell anemia  structure of globin molecule abnormal
    • Quantity compromised  thalassemia  α or β globin chains
  • Biochemical and Molecular Basis of Single Gene (Mendelian) Disorders
    • Genetically Determined Adverse Reactions to Drugs:
    • Some genetic enzyme deficiencies unmasked only after exposure to certain drugs
    • Pharmacogenetics
    • E.g., G6PD deficiency  under normal conditions no disease  but if given some drug like antimalarials  severe hemolysis
  • Disorders Associated with Defects in Structural Proteins
    • Example: Marfan Syndrome
    • Disorder of connective tissues  skeleton, eyes and CVS
    • 1 in 5000, 70 – 85% cases familial, Autosomal Dominant
    • Mostly mis-sense mutations  abnormal fibrillin-1 , dominant negative effect
    • Mutation in FBN1 gene  EC glycoprotein fibrillin-1 defect
    • Defective microfibrils  def. scaffolding and tropoelastin deposition and elastic fiber production
    • MFs abundant in aorta, ligaments and ciliary zonules of eye
    • Patients tall and thin, abnormally long legs and arms, spider-like fingers ( arachnodactyly ), hyperextensible joints
    • Dislocation of ocular lens ( ectopia lentis )
    • Weakness of adventitia and media leads to aortic dilatation, aneurysm of proximal aorta, aortic valvular insufficiency, and aortic dissection, mitral valve prolapse
    • READ OTHER EXAMPLES AND DISEASES FROM THE BOOK YOURSELF