Mutation p.Trp3X and mild phenotype of Becker muscular dystrophy

Introduction: X-linked mutations in the DMD gene lead to muscular dystrophies type Duchenne and Becker, either via loss of function or complete absence of the gene product. Stop mutations in the first exons are generally considered to cause the severe Duchenne phenotype because of a complete interruption of gene translation.

Method: In 11-year-old male patient, elevation of creatine kinase was incidentally found when he was examined for hypercholesterolemia. He is swimming at a competitive level, and clinical examination did not show signs of muscular dystrophy. Sanger sequencing of the DMD gene showed the mutation p.Trp3X. Although affecting exon 1 of the DMD gene, this stop mutation may lead to an alternative activation of translation via a variant start codon in exon 6, resulting in a gene product with almost normal function. Because of this alternate translational initiation codon, patients with mutation p.Trp3X show an exceptionally mild phenotype of Becker muscular dystrophy type. Up to now, 20 patients with this mutation have been registered in the Leiden database, all showing a very mild phenotype with some cases preserved ambulation until the age of 60 years.

Conclusions: The rare mutation p.Trp3X in exon 1 of the DMD gene leads to a gene product with near normal function via an alternate translational initiation codon in exon 6. Patients with this mutation show an exceptionally mild phenotype of Becker muscular dystrophy.