Deficiency of the syntrophins and α-dystrobrevin in patients with inherited myopathy

The syntrophins and dystrobrevins are members of the dystrophin-associated protein complex, and are thought to function as modular adaptors for signalling proteins recruited to the sarcolemmal membrane. We have characterised the expression of the syntrophins (α-, β1-, and β2-) and α-dystrobrevin by immunohistochemistry in normal human muscle and in biopsies from 162 patients with myopathies of unknown aetiology (with normal staining for dystrophin and other dystrophin-associated proteins). Unlike mice, β2-syntrophin is expressed at the sarcolemma in post-natal human skeletal muscle. Deficiency of α-dystrobrevin +/− β2-syntrophin was present in 16/162 (10%) patients, compared to age-matched controls. All patients presented with congenital-onset hypotonia and weakness, although there was variability in clinical severity. Two major clinical patterns emerged: patients with deficiency of β2-syntrophin and α-dystrobrevin presented with severe congenital weakness and died in the first year of life, and two patients with deficiency of α-dystrobrevin had congenital muscular dystrophy with complete external ophthalmoplegia. We have sequenced the coding regions of α-dystrobrevin and β2-syntrophin in these patients, and identified a new isoform of dystrobrevin, but have not identified any mutations. This suggests that disease causing mutations occur outside the coding region of these genes, in gene(s) encoding other components of the syntrophin–dystrobrevin subcomplex, or in gene(s) responsible for their post-translational modification and normal localisation.