ArticleHuman molecular genetics2019
Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 43 citations in OpenAlex.
- Klhl41b orchestrates sarcomere assembly and growth to drive skeletal muscle hypertrophy in vivo.Skeletal muscle · 2026Article
- Human clearance systems have a layered architecture across tissues and cell types that supports varied proteome compositions.Autophagy · 2026Article
- Article
- Temporal Dynamics of the Plasma Proteomic Landscape Reveals Maladaptation in ME/CFS Following Exertion.Molecular & cellular proteomics : MCP · 2025Article
- Proteomic analysis of nemaline myopathy in infants reveals distinct common dysregulated proteins and cellular pathways.Frontiers in neurology · 2025Article
- Article
- Spatial transcriptomics in embryonic mouse diaphragm muscle reveals regional gradients and subdomains of developmental gene expression.iScience · 2024Article
- Nemaline myopathy with scoliosis: a case report.Frontiers in pediatrics · 2024Article
- Article
- NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy.Human molecular genetics · 2023Article
- Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies.Acta neuropathologica communications · 2023Article
- A novel loss-of-function mutation in NRAP is associated with left ventricular non-compaction cardiomyopathy.Frontiers in cardiovascular medicine · 2023Article
- Ubiquitin ligases: guardians of mammalian development.Nature reviews. Molecular cell biology · 2022Review
- The roles of KLHL family members in human cancers.American journal of cancer research · 2022Review
- Molecular and cellular basis of genetically inherited skeletal muscle disorders.Nature reviews. Molecular cell biology · 2021Review
- Single-nucleus RNA-seq identifies transcriptional heterogeneity in multinucleated skeletal myofibers.Nature communications · 2020Article
- Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes.International journal of molecular sciences · 2020Article
- The ubiquitin-proteasome system in regulation of the skeletal muscle homeostasis and atrophy: from basic science to disorders.The journal of physiological sciences : JPS · 2020Review
- Review
- Update on Congenital Myopathies in Adulthood.International journal of molecular sciences · 2020Review
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5 authors at 1 institution in 1 country.
Funding
Abstract
Nemaline myopathy (NM) is the most common form of congenital myopathy that results in hypotonia and muscle weakness. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode for members of the Kelch family of proteins. Kelch proteins act as substrate-specific adaptors for Cullin 3 (CUL3) E3 ubiquitin ligase to regulate protein turnover through the ubiquitin-proteasome machinery. Defects in thin filament formation and/or stability are key molecular processes that underlie the disease pathology in NM; however, the role of Kelch proteins in these processes in normal and diseases conditions remains elusive. Here, we describe a role of NM causing Kelch protein, KLHL41, in premyofibil-myofibil transition during skeletal muscle development through a regulation of the thin filament chaperone, nebulin-related anchoring protein (NRAP). KLHL41 binds to the thin filament chaperone NRAP and promotes ubiquitination and subsequent degradation of NRAP, a process that is critical for the formation of mature myofibrils. KLHL41 deficiency results in abnormal accumulation of NRAP in muscle cells. NRAP overexpression in transgenic zebrafish resulted in a severe myopathic phenotype and absence of mature myofibrils demonstrating a role in disease pathology. Reducing Nrap levels in KLHL41 deficient zebrafish rescues the structural and function defects associated with disease pathology. We conclude that defects in KLHL41-mediated ubiquitination of sarcomeric proteins contribute to structural and functional deficits in skeletal muscle. These findings further our understanding of how the sarcomere assembly is regulated by disease-causing factors in vivo, which will be imperative for developing mechanism-based specific therapeutic interventions.
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