Duchenne/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations

Abstract

The dark-adapted electroretinogram (ERG) of patients with Duchenne and Becker muscular dystrophy (DMD/BMD) shows a marked reduction in b-wave amplitude. Genotype-phenotype studies of mouse models for DMD show position-specific effects of the mutations upon the phenotype: mice with 5' defects of dystrophin have normal ERGs, those with defects in the central region have a normal b-wave amplitude associated with prolonged implicit times for both the b-wave and oscillatory potentials, and mice with 3' defects have a phenotype similar to that seen in DMD/BMD patients. The mouse studies suggest a key role for the carboxyl terminal dystrophin isoform, Dp260, in retinal electrophysiology. We have undertaken a systematic evaluation of DMD/BMD patients through clinical examination and review of the literature in order to determine whether the position-specific effects of mutations noted in the mouse are present in man. We have found that, in man, a wider variation of DMD defects correlate with reductions in the b-wave amplitude. Individuals with normal ERGs have mutations predominantly located 5' of the transcript initiation site of Dp260. Our results suggest that the most important determinant in the ERG b-wave phenotype is the mutation position, rather than muscle disease severity. Forty-six per cent of patients with mutations 5' of the Dp260 transcript start site have abnormal ERGs, as opposed to 94% with more distal mutations. The human genotype-phenotype correlations are consistent with a role for Dp260 in normal retinal electrophysiology and may also reflect the expression of other C-terminal dystrophin isoforms and their contributions to retinal signal transmission.