Makindo Medical Notes

Related Subjects: |DNA replication |DNA structure in Nucleus |Cell Cycle |Mitosis and Meiosis |Ribosomes |Microtubules |Mitochondria |Smooth and Rough Endoplasmic Reticulum

🧬 Genetic mutations are permanent changes in the DNA sequence. They may be germline (inherited, present in all cells) or somatic (acquired, restricted to certain tissues, e.g. cancer). Mutations are a major source of genetic diversity but also underlie many human diseases.

🧾 Types of Genetic Mutations

• Point Mutations 🎯 :
  • Single nucleotide change.
  • Types:
    • Missense → one amino acid replaced by another (e.g. sickle cell anaemia, HBB gene).
    • Nonsense → premature stop codon → truncated protein (e.g. Duchenne muscular dystrophy).
    • Silent → no amino acid change (due to codon redundancy) but may affect splicing or mRNA stability.
• Insertions & Deletions (Indels) ➕➖ :
  • Extra or missing nucleotides.
  • If not multiple of 3 → frameshift → altered reading frame (e.g. Tay-Sachs disease).
• Copy Number Variations (CNVs) 📊 :
  • Large segments duplicated or deleted (e.g. Charcot-Marie-Tooth disease type 1A).
• Chromosomal Mutations 🧩 :
  • Deletions (Cri-du-chat, 5p deletion).
  • Duplications.
  • Inversions.
  • Translocations (Philadelphia chromosome in CML: t(9;22)).
  • Aneuploidy (trisomy 21 → Down syndrome; monosomy X → Turner syndrome).

⚠️ Causes of Mutations

• Spontaneous :
  • Replication errors (mismatch, slippage).
  • Spontaneous base deamination/oxidation.
• Induced :
  • Radiation (UV → thymine dimers; X-rays → double-strand breaks).
  • Chemicals (alkylating agents, tobacco carcinogens).
  • Biological (retroviruses inserting into host genome).

📊 Consequences of Mutations

• Beneficial 🌟 : e.g. CCR5-Δ32 mutation → resistance to HIV.
• Neutral ⚖️ : Silent or non-coding variants with no effect on fitness.
• Harmful ❌ : Disease-causing → cancer (p53 mutation), metabolic disorders, congenital syndromes.

🧪 Examples of Genetic Disorders

• Single-Gene :
  • Cystic fibrosis (CFTR mutations, ΔF508).
  • Sickle cell disease (HBB missense mutation).
  • Huntington’s disease (CAG trinucleotide repeat expansion, HTT gene).
• Chromosomal :
  • Down syndrome (trisomy 21).
  • Turner syndrome (45,X).
  • Klinefelter syndrome (47,XXY).
• Complex / Multifactorial :
  • Diabetes, heart disease, schizophrenia → polygenic + environmental influence.

🔍 Detection & Analysis

• Genetic testing → PCR, Sanger sequencing, FISH, karyotyping, microarrays.
• Next-Generation Sequencing (NGS) → high-throughput, used for cancer panels, rare disease diagnosis.
• Whole exome/genome sequencing → research & clinical applications.

💉 Clinical Relevance

• Personalised Medicine 🎯 :
  • EGFR, KRAS, BRAF mutations → guide targeted cancer therapies.
  • Pharmacogenomics (e.g. TPMT mutation → azathioprine toxicity).
• Gene Therapy 🛠️ :
  • CRISPR-Cas9 and viral vectors used to correct defective genes (e.g. in SCID).
• Cancer 🔬 :
  • Mutations in tumour suppressors (p53, BRCA1/2) and oncogenes (RAS, MYC) drive oncogenesis.
  • Targeted therapies (imatinib in CML, PARP inhibitors in BRCA mutations).

📚 Summary

Genetic mutations may be point, indel, CNV, or chromosomal. They arise spontaneously or from environmental damage. Consequences range from neutral to beneficial to disease-causing. Understanding mutations is vital in genetics, oncology, pharmacology, and personalised medicine.