A physician-validated, board-style question from the Active Transport QBank. Try it, then check the reasoning for every option.
A 5-year-old boy presents to the pediatrician after his parents noted that he could not sustain physical exertion and would experience muscle cramping. It was noted that after physical exertion the boy experienced severe muscle pain. After a series of biochemical and genetic tests, it was discovered the that the boy had a nonsense mutation in the gene encoding the muscle glycogen phosphorylase. Thus he was diagnosed with McArdle's disease. Which of the following mRNA changes would be expected to cause this mutation?
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A
UGU -> CGCIncorrect. UGU (cysteine) → CGC (arginine) is a missense mutation, not a nonsense mutation.
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B
AUG -> UCAIncorrect. AUG (methionine, start codon) → UCA (serine) is a missense mutation affecting initiation; not a nonsense mutation.
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C
CUG -> AUGIncorrect. CUG (leucine) → AUG (methionine) is a missense mutation; AUG is a start codon, not a stop codon.
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D
UAU -> UAACorrect. UAU (tyrosine) → UAA (stop codon) is a nonsense mutation, producing a truncated, non-functional muscle glycogen phosphorylase in McArdle disease.
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E
GCC -> GCAIncorrect. GCC → GCA is a silent (synonymous) mutation — both codons encode alanine — and therefore would not produce the truncated, nonfunctional protein required for McArdle disease.
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Answer: D. A nonsense mutation creates a premature stop codon, prematurely terminating translation and producing a truncated, non-functional protein. Of the three stop codons (UAA, UAG, UGA), only the mutation UAU → UAA converts a codon for tyrosine into the stop codon UAA, making this a nonsense mutation.
Quick mutation-type review: silent mutation (same amino acid encoded — e.g., wobble position change), missense mutation (different amino acid — e.g., UGU→CGC: cysteine→arginine), nonsense mutation (codon→stop), and frameshift (insertion/deletion not divisible by 3, shifting reading frame).
In McArdle disease (GSD V), nonsense or missense mutations in the gene encoding muscle glycogen phosphorylase (PYGM) lead to absent or non-functional enzyme, blocking glycogenolysis in skeletal muscle. Patients show exercise intolerance, muscle cramps after exertion, and characteristic 'second wind' phenomenon. Lab findings include elevated CK after exercise, myoglobinuria, and a flat lactate curve on ischemic forearm exercise test.
**Why each option:**
**A.** UGU (cysteine) → CGC (arginine) is a missense mutation, not a nonsense mutation.
**B.** AUG (methionine, start codon) → UCA (serine) is a missense mutation affecting initiation; not a nonsense mutation.
**C.** CUG (leucine) → AUG (methionine) is a missense mutation; AUG is a start codon, not a stop codon.
**D.** Correct. UAU (tyrosine) → UAA (stop codon) is a nonsense mutation, producing a truncated, non-functional muscle glycogen phosphorylase in McArdle disease.