U01.01.008 Mutations in DNA

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Learning Objectives

  • Differentiate between Transitions and Transversions.
  • Classify point mutations based on their effect on the protein product (Silent, Missense, Nonsense).
  • Understand the severe consequences of Frameshift and Splice Site mutations.
  • Identify clinical examples like Sickle Cell Disease and Huntington’s Disease.

1. Basic Nucleotide Substitutions

Point mutations involve a single base change. The degree of clinical impact generally follows this hierarchy:
Silent << Missense < Nonsense < Frameshift.

  • Transition: Purine to Purine (A ↔ G) or Pyrimidine to Pyrimidine (C ↔ T).
  • Transversion: Purine to Pyrimidine (A ↔ T) or Pyrimidine to Purine (C ↔ G).

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2. Functional Impact of Point Mutations

Mutation Type Molecular Effect Clinical/Example Note
Silent Synonymous change: codes for the same amino acid. Often at the 3rd (wobble) position. No change in protein function.
Missense Codes for a different amino acid. Sickle Cell Disease (Glutamic acid → Valine).
Nonsense Results in a premature stop codon (UGA, UAA, UAG). “Stop the nonsense!” → Usually a nonfunctional, truncated protein.

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3. Frameshift & Structural Mutations

Frameshift Mutation

  • Mechanism: Insertion or deletion of nucleotides not divisible by 3.
  • Effect: Misreading of all downstream nucleotides. Usually results in a very different protein or a premature stop.
  • Examples: Duchenne Muscular Dystrophy, Tay-Sachs, Cystic Fibrosis.

Splice Site Mutation

  • Mechanism: Mutation at the intron-exon junction leads to a retained intron in the mRNA.
  • Examples: Rare cancers, dementia, and β-thalassemia.

Slipped Strand Mispairing (Repeat Expansion)

  • Mechanism: DNA polymerase slips at repetitive regions, adding extra repeats.
  • Clinical Concept: Anticipation (symptoms appear earlier/more severely in successive generations).
  • Example: Huntington’s disease (CAG repeats).

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4. Clinical Mnemonic & Summary

Stop Codons:
1. U Go Away (UGA)
2. U Are Away (UAA)
3. U Are Gone (UAG)

 

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