# Sarcoglycan in Myopathy and Muscle Membrane Stability

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $395,000

## Abstract

PROJECT SUMMARY
The sarcoglycan complex stabilizes the plasma membrane of muscle, and mutations in the genes encoding
sarcoglycan subunits produce a fragile sarcolemma. Sarcolemmal disruption is a general feature of skeletal
and cardiac muscle injury, as well as the myopathic disorders arising from dystrophin or sarcoglycan gene
mutations. This research program has as its primary goal to understand the mechanisms by which dystrophin
and sarcoglycan stabilize the sarcolemma and to identify genetic modifiers of muscular dystrophy. Because
these rare genetic disorders share features with muscle injury, including cardiac muscle injury, we hypothesize
that modifiers of sarcoglycan mutations will not only exert as similar effect on dystrophinopathies but also on
muscle injury in general. We mapped genetic modifiers using a mouse model of sarcoglycanopathy, the Sgcg
model which lacks gamma-sarcoglycan. This model was selected because there was strong evidence for
modifiers in humans with sarcoglycan gene mutations. We used an intercross strategy in Sgcg mice, taking
advantage of the mild protective phenotype seen in the 129 genetic background and the severe phenotype
seen in Sgcg mice on the deleterious DBA background. We successfully identified multiple genetic modifiers
including latent TGFβ binding protein 4 (LTBP4) and annexin A6 (ANXA6). Both modifier genes are
biologically linked to injury repair and recovery and validate the utility of the method. Concomitant with this
progress, there have advances in the development and approval of antisense oligonucleotide-mediated exon
skipping as a therapy for Duchenne Muscular Dystrophy. We developed a similar approach to treat Limb
Girdle Muscular Dystrophy (LGMD) 2C, which is the form of muscular dystrophy from γ-sarcoglycan gene
mutations. In the last period of support, we showed the feasibility of exon skipping in cell lines generated from
multiple patients with LGMD 2C mutations, demonstrating that Mini-gamma, the small internally deleted form of
gamma-sarcoglycan stabilizes the sarcolemma. We will now focus on combining exon skipping together with
modifier approaches to elicit genetic correction and promote sarcolemmal stability. We will develop preclinical
data to support exon skipping and simultaneously demonstrate key biological mechanisms about the
relationship between sarcolemmal stability and muscle growth.

## Key facts

- **NIH application ID:** 10128486
- **Project number:** 5R01HL061322-22
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Elizabeth M McNally
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 1999-07-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128486

## Citation

> US National Institutes of Health, RePORTER application 10128486, Sarcoglycan in Myopathy and Muscle Membrane Stability (5R01HL061322-22). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128486. Licensed CC0.

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