# Chaperone Dysfunction in Myopathy: Connecting Yeast Genetics with Mouse Models

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $678,293

## Abstract

Heat shock proteins (HSPs) or protein chaperones are essential to maintain cellular protein
homeostasis. Mutations of proteins within this network can lead to degenerative diseases
including muscular dystrophy. We have now identified mutations in two domains of an HSP40
co-chaperone, DNAJB6, in an autosomal dominantly inherited Limb Girdle Muscular Dystrophy
(LGMDD1). Our central hypothesis is that LGMDD1 mutations alter the conformation of
DNAJB6 such that the interface between these two domains is disrupted, leading to myofibril
disorganization and muscle dysfunction. Based on our results, we further hypothesize that all
LGMDD1 mutations in DNAJB6 can be rescued by perturbation of Hsp70 interaction or activity.
Thus, our approach is to employ all of the tools we have developed to test these hypotheses. In
order to tackle this challenging problem, we will explore DNAJB6 chaperone function and
dysfunction utilizing multiple systems and the expertise of two PIs. Aim 1 will explore whether
manipulating DNAJB6:HSP70 interactions rescues LGMDD1 phenotypes in mouse models and
human cells. Aim 2 will determine the effect of newly identified LGMDD1-associated DNAJB6 J-
domain mutations on chaperone activity in cellular models. Aim 3 will determine the effect of
LGMDD1 mutations on chaperone and co-chaperone function in vivo and in vitro. Our
preliminary data suggest that we have identified additional therapeutic targets that may be
better tolerated in patients than global inhibitors of Hsp70. The overarching goal of this work is
to leverage our transdisciplinary success to develop therapeutic intervention for patients with
LGMDD1.

## Key facts

- **NIH application ID:** 10121210
- **Project number:** 2R01AR068797-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** HEATHER L TRUE-KROB
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $678,293
- **Award type:** 2
- **Project period:** 2015-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121210

## Citation

> US National Institutes of Health, RePORTER application 10121210, Chaperone Dysfunction in Myopathy: Connecting Yeast Genetics with Mouse Models (2R01AR068797-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10121210. Licensed CC0.

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