Which mutation type tends to cause absent or severely reduced dystrophin in DMD?

• A. Frameshift or nonsense mutations in the DMD gene
• B. In-frame deletions
• C. Missense mutations
• D. Splice site mutations

Answer: (A)

When the reading frame of the DMD gene is disrupted in a way that creates a premature stop codon or shifts every downstream codon, no functional dystrophin is produced at the muscle membrane. Frameshift mutations alter the grouping of codons, leading to a truncated, unstable protein that’s typically degraded and missing at the membrane. Nonsense mutations directly introduce a stop signal, yielding a very short, nonfunctional dystrophin. This loss of dystrophin at the muscle surface is what underlies Duchenne muscular dystrophy’s severe phenotype.

In contrast, in-frame deletions remove amino acids but keep the reading frame intact, so a shorter yet partially functional dystrophin can be made, which usually results in Becker muscular dystrophy rather than Duchenne. Missense mutations change a single amino acid and often still allow a largely functional dystrophin protein. Splice site mutations can disrupt splicing in various ways, potentially producing abnormal or truncated dystrophin, but their effect is not as consistently associated with complete absence as frameshift or nonsense mutations.