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 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

SUBMITTER: Mohar NP 

PROVIDER: S-EPMC12007578 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature