# Novel knock-in mouse models of ALS and myopathy-linked Matrin 3 mutations

> **NIH NIH R21** · ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER · 2020 · $435,387

## Abstract

Project Summary:
 The nuclear protein Matrin 3 has many roles in RNA processing including splicing and transport,
and mutations in Matrin 3 gene (MATR3) have been linked to familial forms of amyotrophic lateral
sclerosis (ALS) and distal myopathy with vocal cord and pharyngeal weakness (VCPDM). However, the
exact role of MATR3 in ALS and myopathy is not understood. While 13 pathogenic mutations in MATR3
have been linked to ALS, the S85C mutation can induce either ALS or myopathy. Protein interactome
studies have demonstrated that Matrin 3 interacts with numerous proteins involved in RNA processing.
This is particularly important as RNA processing alterations have been demonstrated to be a common
theme in various forms of ALS including familial forms with mutations in RNA-binding proteins such as
TDP-43, FUS, and C9ORF72. Thus, studying the mechanisms of MATR3 driven pathogenesis has potential
to elucidate the role of RNA binding-proteins and RNA processing in the neuron-muscular disease process.
To investigate the role of MATR3 mutations in ALS and myopathy pathogenesis and disease progression
we have recently generated novel knock-in mouse models that express either the S85C (ALS/VCPDM
associated) or P154S (ALS associated) mutations, which we previously demonstrated led to changes in
Matrin 3 protein interactions and RNA transport deficits in cultured cells. These mouse models were
generated in collaboration with The Jackson Laboratory using CRISPR-Cas in order to avoid overexpression
and maintain physiologic levels of Matrin 3, in contrast to most mouse models that overexpress
transgenes. We hypothesize that MATR3 mutations cause RNA processing deficits which contribute to
motor neuron (ALS) and muscle (myopathy) centric disease. Utilization of our novel mouse models with
mutations inserted in the endogenous MATR3 gene will permit characterization of functional and
molecular consequences of MATR3 mutations. Completion of this work will provide the field with two
new mouse models for the study of disease mechanisms and therapeutic development.

## Key facts

- **NIH application ID:** 10129166
- **Project number:** 1R21NS116385-01A1
- **Recipient organization:** ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
- **Principal Investigator:** ROBERT P BOWSER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $435,387
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129166

## Citation

> US National Institutes of Health, RePORTER application 10129166, Novel knock-in mouse models of ALS and myopathy-linked Matrin 3 mutations (1R21NS116385-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129166. Licensed CC0.

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