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Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2013 Jul 11; Vol. 93 (1), pp. 6-18. Date of Electronic Publication: 2013 Jun 06. - Publication Year :
- 2013
-
Abstract
- Nemaline 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. 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 a key role in muscle development and function. 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.<br /> (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Substitution
Animals
Asian People genetics
Cohort Studies
Frameshift Mutation
Genes, Recessive
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Muscle Proteins genetics
Myopathies, Nemaline ethnology
Myopathies, Nemaline pathology
Pedigree
Polymorphism, Single Nucleotide
Severity of Illness Index
Zebrafish genetics
Muscle Proteins metabolism
Muscle, Skeletal pathology
Mutation, Missense
Myopathies, Nemaline genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 93
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 23746549
- Full Text :
- https://doi.org/10.1016/j.ajhg.2013.05.004