A genetic variant in <i>SMAD7</i> acts as a modifier of <i>LMNA</i>-associated muscular dystrophy, implicating SMAD signaling as a therapeutic target.

Abstract

Mutations in <i>LMNA</i> cause multiple types of muscular dystrophy (<i>LMNA</i>-MD). The symptoms of <i>LMNA</i>-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 <i>LMNA</i> mutation with differing degrees of skeletal muscle disease severity. We identified a variant in <i>SMAD7</i> that segregated with severe muscle disease. To functionally test the <i>SMAD7</i> variant, we generated a <i>Drosophila</i> model possessing the <i>LMNA</i> mutation and the <i>SMAD7</i> variant in the orthologous fly genes. The <i>SMAD7</i> variant increased SMAD signaling and enhanced muscle defects caused by the mutant lamin. Conversely, overexpression of wild-type <i>SMAD7</i> rescued muscle function. These findings were extended to humans by showing that SMAD signaling is increased in muscle biopsy tissue from individuals with <i>LMNA</i>-MD compared to age-matched controls. Collectively, our findings support <i>SMAD7</i> as the first functionally tested genetic modifier for <i>LMNA</i>-MD and suggest components of the SMAD pathway as therapeutic targets.