ORIGIN 1 malgleqaee qrlyqqtllq dglkdmldhg kfldcvvrag erefpchrlv laacspyfra 61 rflaeperag elhleevspd vvaqvlhyly tseialdeas vqdlfaaahr fqipsiftic 121 vsflqkrlcl snclavfrlg llldcarlav aardficahf tlvardadfl glsadeliai 181 issdglnvek eeavfeavmr wagsgdaeaq aerqralptv fesvrcrllp raflesrver 241 hplvraqpel lrkvqmvkda hegrittlrk kkkgkdgaga keadkgtska kaeedeeaer 301 ilpgilndtl rfgmflqdli fmiseegava ydpaanecyc aslsnqvpkn hvslvtkenq 361 vfvagglfyn ednkedpmsa yflqfdhlds ewlgmpplps prclfglgea lnsiyvvggr 421 eikdgercld svmcydrlsf kwgesdplpy vvyghtvlsh mdlvyviggk gsdrkclnkm 481 cvydpkkfew kelapmqtar slfgatvhdg riivaagvtd tgltssaevy sitdnkwapf 541 eafpqerssl slvslvgtly aiggfatlet esgelvptel ndiwryneee kkwegvlrei 601 ayaagatflp vrlnvlcltk m //
- Identification of KLHL40 mutations by targeted next-generation sequencing facilitated a prenatal diagnosis in a family with three consecutive affected fetuses with fetal akinesia deformation sequence (FADS) . Chen TH, et al. Prenat Diagn, 2016 Dec. PMID 27762439
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Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.
Ravenscroft G, et al. Am J Hum Genet, 2013 Jul 11. PMID 23746549, Free PMC ArticleNemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence (FADS). We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays, Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM.
Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. - Nemaline Myopathy North KN, et al. , 1993. PMID 20301465
- KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy. Garg A, et al. J Clin Invest, 2014 Aug. PMID 24960163, Free PMC Article
- KLHL40 lokalisoituu sarkomeerin I ja A raitaan ja sitoutuu nebuliiniin (NEB), joka on usein osaoitettavissa NM taudissa kuten ohut filamentti proteiini leiomodiini3.KLHL40 edistää NEB ja LMOD3:n stabiiliutta ja blokeeraa LMOD3:n ubikitinaation. Jos KLHL40 puuttuu, NEB ja LMOD3 määrät ovat alentuneet luurankolihaksissa. Nemaliinimyopatian tausta lienee sarkomeerin ohuen filamentin proteiinien katoaminen niiltä, joilla KLHL40 geenivaikutus puuttuu.
- 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.
- Update on the Kelch-like (KLHL) gene family. Dhanoa BS, et al. Hum Genomics, 2013 May 15. PMID 23676014, Free PMC Article
https://www.genecards.org/cgi-bin/carddisp.pl?gene=KLHL40
Aliases for KLHL40 Gene
External Ids for KLHL40 Gene
- HGNC: 30372
- Entrez Gene: 131377
- Ensembl: ENSG00000157119
- OMIM: 615340
- UniProtKB: Q2TBA0
Previous HGNC Symbols for KLHL40 Gene
- KBTBD5
Previous GeneCards Identifiers for KLHL40 Gene
- GC03P042727
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