ArticleThe Journal of clinical investigation2014
KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 127 citations in OpenAlex.
- Prenatal Diagnosis and Functional Analysis of Two Compound Heterozygous Variants in the KLHL40 Gene Causing Nemaline Myopathy 8.Molecular genetics & genomic medicine · 2026Article
- Post-infarction KLHL40-mediated regulation of cardiac sarcomeric integrity and function.PeerJ · 2026Article
- Human clearance systems have a layered architecture across tissues and cell types that supports varied proteome compositions.Autophagy · 2026Article
- Integrative Approaches to Myopathies and Muscular Dystrophies: Molecular Mechanisms, Diagnostics, and Future Therapies.International journal of molecular sciences · 2025Review
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- Time-series transcriptomics reveals distinctive mRNA expression dynamics associated with gene ontology specificity and protein expression in skeletal muscle after electrical stimulation-induced resistance exercise.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Exploring the Molecular Mechanism of Skeletal Muscle Development in Ningxiang Pig by Weighted Gene Co-Expression Network Analysis.International journal of molecular sciences · 2024Article
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- Transcriptome-Based Identification of the Muscle Tissue-Specific Expression GeneAnimals : an open access journal from MDPI · 2023Article
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- Whole exome sequencing improves genetic diagnosis of fetal clubfoot.Human genetics · 2023Article
- Case report: Homozygous variants ofFrontiers in genetics · 2023Article
- Transcriptomic analysis of paired healthy human skeletal muscles to identify modulators of disease severity in DMD.Frontiers in genetics · 2023Article
- Combining Gene Mutation with Expression of Candidate Genes to Improve Diagnosis of Escobar Syndrome.Genes · 2022Article
- Morphological and Molecular Responses ofInternational journal of molecular sciences · 2022Article
- The Mechanisms of Thin Filament Assembly and Length Regulation in Muscles.International journal of molecular sciences · 2022Review
15 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
Abstract
Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, but the mechanistic basis of their contribution to disease remains unresolved. Here, we demonstrated that loss of a muscle-specific protein, kelch-like family member 40 (KLHL40), results in a nemaline-like myopathy in mice that closely phenocopies muscle abnormalities observed in KLHL40-deficient patients. We determined that KLHL40 localizes to the sarcomere I band and A band and binds to nebulin (NEB), a protein frequently implicated in NM, as well as a putative thin filament protein, leiomodin 3 (LMOD3). KLHL40 belongs to the BTB-BACK-kelch (BBK) family of proteins, some of which have been shown to promote degradation of their substrates. In contrast, we found that KLHL40 promotes stability of NEB and LMOD3 and blocks LMOD3 ubiquitination. Accordingly, NEB and LMOD3 were reduced in skeletal muscle of both Klhl40-/- mice and KLHL40-deficient patients. Loss of sarcomere thin filament proteins is a frequent cause of NM; therefore, our data that KLHL40 stabilizes NEB and LMOD3 provide a potential basis for the development of NM in KLHL40-deficient patients.
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