A nonsense mutation at codon 150 of the β‑globin gene introduces a premature stop codon (UAA). Explain how this mutation affects β‑globin mRNA stability, protein synthesis, and the clinical phenotype seen in β‑thalassemia major.
Answer
The mutation triggers nonsense‑mediated decay of the β‑globin mRNA and produces a truncated β‑chain lacking the C‑terminus, leading to severe anemia with transfusion dependence.
Step-by-step solution
- The mutation converts a codon for an amino acid into the stop codon UAA at position 150.
- During translation, ribosomes terminate prematurely, producing a truncated β‑globin peptide lacking the C‑terminal region.
- Premature termination signals the cell’s nonsense‑mediated decay (NMD) pathway to degrade the aberrant β‑globin mRNA, reducing its abundance.
- With fewer β‑globin chains, the balance between α‑ and β‑chains is disturbed; excess free α‑chains precipitate, damaging red‑cell membranes.
- Red‑cell precursors undergo ineffective erythropoiesis, causing severe anemia (β‑thalassemia major).
- Clinically, patients exhibit transfusion dependence, bone deformities, and extramedullary hematopoiesis.
Common mistake: Assuming the truncated protein is functional or neglecting the role of mRNA decay.
Concept tested: Nonsense mutation consequences
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