A genetic variant in acts as a modifier of -associated muscular dystrophy, implicating SMAD signaling as a therapeutic target.

Mutations in cause multiple types of muscular dystrophy (-MD). The symptoms of -MD are highly variable and sensitive to genetic background. To identify genetic contributions to this phenotypic variability, we performed whole-genome sequencing on four siblings possessing the same mutation with differing degrees of skeletal muscle disease severity. We identified a variant in that segregated with severe muscle disease. To functionally test the variant, we generated a model possessing the mutation and the variant in the orthologous fly genes. The variant increased SMAD signaling and enhanced muscle defects caused by the mutant lamin. Conversely, overexpression of wild-type rescued muscle function. These findings were extended to humans by showing that SMAD signaling is increased in muscle biopsy tissue from individuals with -MD compared to age-matched controls. Collectively, our findings support as the first functionally tested genetic modifier for -MD and suggest components of the SMAD pathway as therapeutic targets.