Genetics · MU Sofia

10. Pathogenesis of monogenic disorders: mutations affecting enzymes, receptors and structural proteins; gene interactions, epistasis.

Inside: 9 sections · 8 labelled pictures · 6 min

Topic 10 of 79 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 9 sections, about 824 words (6 min of reading).

In this note

  1. Monogenic Defects, Mutagenesis, Mosaicism, Types of Mutations, and Phenotypic Expression
  2. I. Monogenic Defects
  3. II. Mutagenesis
  4. III. Germline vs. Somatic Mutations
  5. IV. Mosaicism
  6. V.
  7. Classification of Mutations in the Human Genome
  8. VI. Phenotypic Expression of Mutations
  9. VII. Clinical Relevance

I. Monogenic Defects

  • Definition: Diseases caused by a mutation in a single gene locus. Despite being caused by only one defective gene, they can have systemic effects.
  • Modes of inheritance:
  • Autosomal dominant (AD): One mutated allele is enough for disease. Often due to gain-of-function or dominant-negative mutations.
  • Example: Marfan syndrome → mutation in FBN1 gene (fibrillin-1). Defective microfibrils lead to weak connective tissue, affecting the aorta, skeleton, and eyes.
  • Example: Huntington disease → CAG repeat expansion in HTT gene → toxic gain-of-function polyglutamine tract.
  • Autosomal recessive (AR): Both alleles must be mutated. Usually loss-of-function of enzymes.
  • Example: Cystic fibrosis → CFTR mutation → defective chloride channel → mucus accumulation.
  • Example: Phenylketonuria (PKU) → PAH mutation → phenylalanine hydroxylase deficiency → toxic accumulation of phenylalanine.
  • X-linked: Mutations on the X chromosome. Males more affected (hemizygous).
  • Example: Duchenne muscular dystrophy → frameshift in DMD gene → absent dystrophin protein.
  • Example: Hemophilia A → F8 mutation → factor VIII deficiency.

Key concept: Even a single-gene defect can disrupt whole biochemical pathways → multisystem disease.

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