Makindo Medical Notes

🧬 The human genome contains genes of vastly different sizes — for example, the Beta globin gene is only 1,400 bases long, while the dystrophin gene spans an enormous 2.4 million bases. These differences highlight how gene length, complexity, and function vary widely across the genome, with major implications for disease when mutations occur.

📖 About Gene Structure

• 🚦 Promoter Site:
  • A DNA "control switch" at the start of a gene.
  • Binds RNA polymerase and transcription factors to initiate transcription.
  • Without a working promoter, the gene remains "silent." ➡️ No RNA ➡️ No protein.
  • Clinical relevance: Mutations in the β-globin promoter cause β-thalassemia, leading to reduced or absent haemoglobin production.
• 🖋 RNA Polymerase II:
  • The main enzyme that copies DNA into messenger RNA (mRNA).
  • Highly specialised for protein-coding genes.
  • Clinical relevance: Targeted by toxins (e.g., α-amanitin from poisonous mushrooms), leading to fatal liver failure.
• 🔑 Promoter Sequences:
  • Act like “landing pads” to guide RNA polymerase.
  • Key elements include:
    • 📍 TATA Box: (~25–35 bases upstream). Critical for accurate transcription start. Mutations here can silence genes.
    • 📍 GC Box: Upstream enhancer sequence, important in housekeeping genes that must stay “on” all the time.
  • Clinical relevance: Fragile X syndrome involves repeat expansions near promoter regions, silencing the FMR1 gene.
• 🚀 Start Site for Transcription:
  • The exact “launch pad” where RNA synthesis begins.
  • Defines the 5’ end of mRNA.
  • Clinical relevance: Mutations here may create abnormal start sites, producing defective proteins.
• 🧩 Exons:
  • Protein-coding sequences that remain in mature mRNA.
  • Spliced together like Lego blocks to form the final transcript.
  • Clinical relevance: Exon deletions in the dystrophin gene cause Duchenne muscular dystrophy (DMD), leading to absent or truncated dystrophin protein.
• 🚫 Introns:
  • Non-coding “spacers” between exons.
  • Removed during RNA splicing, but play a role in regulation and alternative splicing.
  • Allow a single gene to produce multiple protein isoforms ➡️ more diversity from fewer genes.
  • Clinical relevance: Mis-splicing of introns causes conditions such as spinal muscular atrophy (SMA) and some cancers.
• ⛔ Stop Site for Transcription:
  • Signals RNA polymerase to “stop copying.”
  • Prevents wasteful or harmful transcription beyond the gene.
  • Clinical relevance: Mutations that disrupt stop codons can cause “run-on” transcripts, producing abnormally long proteins linked to disease (e.g., some types of muscular dystrophy).

💡 Clinical Relevance – Why Gene Structure Matters

• Inherited Blood Disorders: Mutations in the β-globin gene (promoter, exons, or splicing sites) ➡️ Thalassemia or Sickle Cell Disease.
• Neuromuscular Disease: The huge dystrophin gene is prone to deletions ➡️ Duchenne Muscular Dystrophy.
• Cancer: Promoter methylation can silence tumour suppressor genes (e.g., BRCA1), driving cancer progression.
• Personalised Medicine: Knowing exon/intron variants helps tailor gene therapy and RNA-based treatments (e.g., exon-skipping therapies in DMD).