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

Nathaniel P Mohar; Christopher J Langland; Zachary Darr; Jill Viles; Steven A Moore; Benjamin W Darbro; Lori L Wallrath

doi:10.1126/sciadv.ads7903

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

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

Nathaniel P Mohar, Christopher J Langland, Zachary Darr, Jill Viles, Steven A Moore, Benjamin W Darbro and Lori L Wallrath

Science advances, Vol.11(16), eads7903

04/18/2025

DOI: 10.1126/sciadv.ads7903

PMCID: PMC12007578

PMID: 40249815

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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.

Mutation

Signal Transduction

Adult

Animals

Disease Models, Animal

Female

Humans

Lamin Type A - genetics

Male

Muscle, Skeletal - metabolism

Muscle, Skeletal - pathology

Muscular Dystrophies - genetics

Muscular Dystrophies - metabolism

Muscular Dystrophies - pathology

Smad7 Protein - genetics

Smad7 Protein - metabolism

Details

Title: Subtitle: A genetic variant in SMAD7 acts as a modifier of LMNA -associated muscular dystrophy, implicating SMAD signaling as a therapeutic target
Creators: Nathaniel P Mohar - University of Iowa
Christopher J Langland - University of Iowa
Zachary Darr - Department of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Jill Viles - Independent researcher, Gowrie, Iowa, USA
Steven A Moore - University of Iowa
Benjamin W Darbro - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Lori L Wallrath - Department of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Science advances, Vol.11(16), eads7903
DOI: 10.1126/sciadv.ads7903
PMID: 40249815
PMCID: PMC12007578
NLM abbreviation: Sci Adv
ISSN: 2375-2548
eISSN: 2375-2548
Publisher: AMER ASSOC ADVANCEMENT SCIENCE; WASHINGTON
Grant note: National Institutes of Health-NIAMS grant: R21AR075193 Muscular Dystrophy Association Research Grant: 22-1061420 National Institutes of Health-GM grant: T32GM144636 Paul D. Wellstone Muscular Dystrophy Specialized Research Center NIH grant: 1U54NS053672 American Heart Association Predoctoral Fellowship: 25PRE1373209
This work was supported by the National Institutes of Health-NIAMS grant #R21AR075193 (to L.L.W. and B.W.D.), the Muscular Dystrophy Association Research Grant 22-1061420 (to L.L.W.), the National Institutes of Health-GM grant #T32GM144636 (to N.P.M.), the Paul D. Wellstone Muscular Dystrophy Specialized Research Center NIH grant #1U54NS053672 (to S.A.M.), and the American Heart Association Predoctoral Fellowship 25PRE1373209 (to N.P.M.)
Language: English
Date published: 04/18/2025
Academic Unit: Stead Family Department of Pediatrics; Pathology; Medical Genetics and Genomics; Biochemistry and Molecular Biology; University College Courses
Record Identifier: 9984811215202771

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