This document discusses the biochemical and molecular basis of single gene or Mendelian disorders. It explains that these disorders can be caused by mutations that affect protein or gene product synthesis, including transcription, mRNA processing, and translation. It provides examples of how abnormal proteins can directly or indirectly influence phenotype. Specific mechanisms covered include enzyme defects, defects in membrane receptors and transport systems, alterations in non-enzyme proteins, and genetically determined adverse drug reactions. Marfan syndrome is used as an example of a disorder of structural proteins caused by a mutation in the FBN1 gene for fibrillin-1.

2. Genetic Disorders Biochemical and Molecular Basis of Single Gene (Mendelian) Disorders Dr. Shahab Riaz

3. 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

4. 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

5. 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)

6. 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

7. 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

8. 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

9. 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

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