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

Abstract

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