Dystrophin nonsense mutation induces different levels of exon 29 skipping and leads to variable phenotypes within one BMD family

Within one X-linked muscular dystrophy family, different phenotypes for thr ee males occurred: (1) a severely affected Becker patient with cardiomyopat hy, (2) a mildly affected Becker patient, and (3) an apparently healthy mal e with elevated serum CK levels. In the muscle biopsy specimen of patient 2 one out of four antibodies (NCL-DYS1) showed absence of dystrophin. The pr otein truncation test detected a truncated dystrophin for both muscle tissu e and lymphocytes of this patient next to an additional near normal size fr agment in muscle. Genomic sequence analysis revealed a nonsense mutation in exon 29 (4148C > T) of the dystrophin gene. Sequence analysis of the mRNA fragment of the larger peptide showed skipping of exon 29, restoring an ope n reading frame. Consequently, the epitope of the antibody NCL-DYS1 is mapp ed to exon 29. The variable clinical features of the three relatives from h ealthy to severely affected therefore seems to be related to the level of s kipping of exon 29. This finding underscores the future potential of gene t herapeutic strategies aimed at inducing exon skipping in Duchenne muscular dystrophy, to generate a much milder disease.