Molecular Basis of Genetic Diseases

Foundations of Genetic Disease - Gene Glitches 101

• Mutation: Permanent DNA alteration; frequency <1%.
• Polymorphism: Common DNA variation; frequency >1%.
• Penetrance: Proportion of individuals with a specific genotype who express the expected phenotype. All-or-none.
• Expressivity: Variation in phenotypic expression (severity/type) among individuals with the same genotype. Variable.
• Classifications:
  • Monogenic: Single gene defect (e.g., Cystic Fibrosis).
  • Polygenic: Multiple genes + environment (e.g., Type 2 Diabetes).
  • Chromosomal: Numerical/structural anomalies (e.g., Trisomy 21).
  • Mitochondrial: Maternally inherited (e.g., LHON).

⭐ Pleiotropy refers to a single gene influencing multiple, often seemingly unrelated, phenotypic traits (e.g., Marfan syndrome).

Mutation Mayhem - DNA's Dark Side

• Point Mutations (Single Base Change):
  • Silent: Different codon, same amino acid (AA).
  • Missense: Different codon, different AA (e.g., Sickle cell: HbS, $GAG \rightarrow GTG$, Glu→Val).
  • Nonsense: Codon becomes STOP (UAA, UAG, UGA). 📌 "U Are Away, U Go Away, U Are Gone". Yields truncated protein.
• Frameshift Mutations (Insertions/Deletions not multiple of 3 bases):
  • Alters reading frame downstream; often premature STOP.
• Functional Consequences:
  • Loss-of-Function (LOF): Reduced or absent protein function (typically recessive).
  • Gain-of-Function (GOF): Increased or novel protein function (typically dominant).
  • Dominant Negative: Mutant interferes with wild-type function.

⭐ Nonsense mutations often trigger nonsense-mediated mRNA decay (NMD), a quality control degrading faulty mRNAs.

Inheritance Patterns & Exemplars - Family Fault Lines

• Pedigree Analysis: Visualizes gene transmission.
• Key Distinctions:

⭐ Anticipation: Disease worsens or appears earlier in successive generations. Common in trinucleotide repeat disorders (e.g., Huntington's [AD], Myotonic Dystrophy [AD], Fragile X [XLD]).

📌 Mnemonic AD/AR: "Dominant diseases Destroy Generations (Vertical). Recessive diseases Run in sibs (Horizontal)."

Chromosomal Chaos & Diagnostics - Blueprint Blunders

• Numerical Abnormalities (Aneuploidy): Gain/loss of chromosomes.
  • Down Syndrome: Trisomy 21. 📌 Mnemonic: Voting age 21 (Down for voting).
  • Turner Syndrome: 45,XO (females, short stature).
  • Klinefelter Syndrome: 47,XXY (males, gynecomastia).
• Structural Abnormalities: Altered chromosome structure.
  • Translocations: e.g., Philadelphia Chromosome t(9;22) in CML.
  • Deletions: e.g., Cri-du-chat syndrome (del 5p).
• Key Diagnostics:
  • Karyotyping: Visualizes chromosome number & structure.
  • FISH: Detects specific DNA sequences/regions.
  • PCR: Amplifies DNA for mutation detection.

⭐ The Philadelphia chromosome, t(9;22)(q34;q11.2), creating the BCR-ABL1 fusion gene, is a hallmark of Chronic Myeloid Leukemia (CML).

High‑Yield Points - ⚡ Biggest Takeaways

• Single-gene disorders follow Mendelian inheritance (AD, AR, X-linked).
• Trinucleotide repeat expansions cause Huntington's (CAG) & Fragile X syndrome (CGG).
• Mitochondrial diseases: maternal inheritance, affect high-energy tissues.
• Genomic imprinting: differential expression by parental origin (e.g., Prader-Willi, Angelman).
• Loss-of-function mutations: common in recessive diseases; gain-of-function in dominant ones.
• Epigenetic changes (e.g., methylation) alter gene expression, causing disease without DNA sequence change.