Background: Mutations in LMNA cause a collection of diseases known as laminopathies, which include multiple types of muscular dystrophy (LMNA-MD). The symptoms of LMNA-MD are sensitive to genetic background, as individuals with the same LMNA mutation can have distinct diagnoses and/or variable disease severity. Here, we describe a family in which four siblings with the same LMNA mutation present with Emery-Dreifuss muscular dystrophy (EDMD) with highly variable severity.
Objective: Our goal is to identify genetic modifiers of LMNA-associated EDMD that drive the variable disease presentation in the family.
Results: Using whole genome sequencing, we identified a variant in the SMAD7 gene, which encodes a negative regulator of the SMAD signaling pathway, present only in the severely affected siblings. To functionally test the SMAD7 variant, we generated a Drosophila model containing both the LMNA mutation and SMAD7 variant in their respective Drosophila orthologs. We demonstrate that the SMAD7 variant has minimal effects on muscle function alone. However, in combination with the LMNA mutation, the SMAD7 variant enhances muscle defects, consistent with a genetic modifier. In addition, the SMAD7 variant enhances activation of the SMAD signaling pathway in muscle, suggesting a mechanism for the enhanced muscle disease severity. Further supporting this mechanism, we demonstrate that overexpression of wild type SMAD7 reduces SMAD signaling and rescues muscle defects in the Drosophila model, implicating the SMAD pathway as a therapeutic target. To broaden our analysis, we sequenced the SMAD7 gene in a cohort of 45 individuals with LMNA-MD and identified six additional variants, two of which map to a crucial SMAD7 regulatory domain.
Conclusions: Collectively, our findings support SMAD7 as a modifier gene for LMNA-MD and the SMAD signaling pathway as a therapeutic target for the disease.