# Kelch proteins in skeletal muscle development and diseases > **NIH NIH R56** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $391,019 ## Abstract SUMMARY Mutations in a large number of proteins associated with the development or maintenance of skeletal muscle result in disease states. Nemaline myopathy (NM) is the most common congenital myopathy that results in hypotonia and muscle weakness associated with the presence of protein aggregates in skeletal muscle. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode members of the Kelch family of proteins. Kelch proteins act as substrate-specific-adapters for Cul3 ubiquitin ligase to regulate protein turn-over through ubiquitin-proteasome machinery. Mutations in several other Kelch proteins have also been identified recently in human myopathies. A fundamental question in the field is how Kelch proteins contribute to skeletal muscle growth and maintenance. This gap in knowledge currently hinders the development of therapeutic strategies for NM and related myopathies. Our long-term goal is to study the function of genes that leads to muscle defects in congenital muscle diseases and to identify critical intervention points to abrogate muscle weakness and neonatal lethality. Our preliminary studies suggest that Kelch proteins regulate dynamic changes in protein networks that are critical for skeletal muscle development and function. In this proposal, we seek to identify the KLHL41-dependent critical points in skeletal muscle development and the mechanism by which mutations lead to structural and functional defects. Our central hypothesis is that KLHL41-mediated ubiquitination of specific factors is central to muscle development in the myoblasts differentiation by regulating myogenic transcription program, and; in the sarcomere assembly by regulating thin-filament chaperones and sarcomeric proteins that are necessary for the formation of functional myofibers. We further hypothesize that KLHL41 mutations disrupt the activation and recycling of the core CUL3-NEDD8- CSN ubiquitination protein complex in skeletal muscle and limit the availability of CUL3 protein complex for other Kelch proteins in muscle. This hypothesis will be tested by three Specific Aims. In Aim 1, we will determine the role of KLHL41 during myoblast differentiation through the regulation of the transcription machinery. Aim 2 will focus on understanding how KLHL41 regulates thin-filament formation and maintenance during myofibrillogenesis in vivo and how specific steps of this process are perturbed by NM-causing mutations. Aim 3 will determine the mechanistic regulation of the CUL3-NEDD8-CSN ubiquitination complex in skeletal muscle. Mutations in genes regulating ubiquitination and protein turn-over processes are increasingly identified in human myopathies and the work proposed here will identify how this process impacts early muscle development, an area that is currently poorly understood. The proposed research is significant because it will help to identify the cellular and molecular origin of myogenic defects that contribute ... ## Key facts - **NIH application ID:** 10479352 - **Project number:** 1R56AR077017-01A1 - **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL - **Principal Investigator:** Vandana Gupta - **Activity code:** R56 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $391,019 - **Award type:** 1 - **Project period:** 2021-09-23 → 2023-09-22 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10479352 ## Citation > US National Institutes of Health, RePORTER application 10479352, Kelch proteins in skeletal muscle development and diseases (1R56AR077017-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10479352. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*