Dysferlin aggregation in limb‐girdle muscular dystrophy type 2B/myoshi myopathy necessitates mutational screen for diagnosis

INTRODUCTION: Diagnosis of the limb-girdle muscular dystrophies (LGMDs) has been facilitated by the use of immunofluorescence microscopy, Western blot analysis, and rapid genetic testing. METHODS: We identified 7 patients with LGMD2B or Miyoshi myopathy (MM) phenotypes and performed detailed history, physical examination, and mutation analyses of genomic DNA. RESULTS: Ten disease-causing variants of the dysferlin gene (DYSF) were detected, 4 of which were novel and predicted to be pathogenic (IVS33+9G>T, c.1343T>C, c.4747T>G, and c.5066dupC). Two of these mutations (c.1343T>C and IVS33+9G>T) were associated with a reduction in sarcolemmal dysferlin expression, despite increased total mRNA and protein in mixed muscle homogenates, due to a pathological retention of the mutated polypeptide in the cytoplasm. CONCLUSIONS: Considering that protein-based assays may yield false negative test results and that dysferlin aggregation may be present in other LGMDs, mutational screening is necessary for specific diagnosis in primary dysferlinopathy patients exhibiting this phenotype.