# Smad signaling in skeletal muscle laminopathies

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2020 · $203,940

## Abstract

Scientific Abstract
Mutations in the human LMNA gene encoding lamins cause skeletal muscular dystrophy that
exhibits a wide range of disease severity, even among family members possessing the identical
mutation. This observation suggests the action of modifier genes. To identify candidate modifier
genes, whole genome sequencing (WGS) was performed on members of a family with LMNA
Emery-Dreifuss muscular dystrophy (EDMD2) (c.1580G>C; p.R527P). The analysis revealed a
novel variant in the SMAD7 gene (c.932A.G; p.Q311R) that segregated with disease severity.
SMAD7 encodes an inhibitor of the conserved TGF-β/Smad signaling pathway. Activation of this
pathway due to reduced levels of SMAD7 represses muscle growth and differentiation and causes
loss of muscle tissue homeostasis. Using a Drosophila model of LMNA muscular dystrophy, we
found that over-expression of the Drosophila orthologue of SMAD7 suppressed lethality caused
by mutant lamins. To test the hypothesis that Smad signaling modifies muscle phenotypes
induced by mutant lamins, we will 1) alter Smad signaling and assay for effects on muscle
phenotypes in Drosophila models of LMNA muscle disease and 2) perform WGS on another
family with an LMNA mutation in which members exhibit either severe or asymptomatic muscle
disease phenotypes. In addition, we will analyze TGF-β/Smad signaling in muscle biopsy tissue
from individuals with LMNA muscular dystrophy. Collectively, our experiments will determine the
interplay between TGF-β/Smad signaling and lamins in skeletal muscle disease and identify
candidate modifier genes are potential targets for therapy. Our discoveries have the potential for
broad impact as individuals with LMNA muscle disease have symptoms of common diseases
such as diabetes and metabolic syndrome.

## Key facts

- **NIH application ID:** 9895098
- **Project number:** 1R21AR075193-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Lori L Wallrath
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $203,940
- **Award type:** 1
- **Project period:** 2020-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895098

## Citation

> US National Institutes of Health, RePORTER application 9895098, Smad signaling in skeletal muscle laminopathies (1R21AR075193-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9895098. Licensed CC0.

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