Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 93, Issue 6, Pages 1108-1117Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2013.10.020
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Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases of National Institute of Health [K01 AR062601]
- Muscular Dystrophy Association of USA [MDA201302]
- National Institutes of Health grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR044345]
- AUism Charitable Foundation
- Foundation Building Strength
- National Health and Medical Research Council of Australia Early Career Researcher Fellowship [1035955]
- Association Francaise contre les Myopathies
- Dubai-Harvard Foundation for Medical Research Collaborative Research Grant
- UWA Collaborative Research Award
- Great Ormond Street Hospital Children's Charity
- University of Western Australia Postgraduate Awards
- National Institutes of Health [P30 HD18655]
- [APP1002147]
- [APP1022707]
- Grants-in-Aid for Scientific Research [24118001, 24118007, 24118005] Funding Source: KAKEN
- Medical Research Council [MR/K000608/1] Funding Source: researchfish
- Muscular Dystrophy UK [RA4/924, RA4/0924] Funding Source: researchfish
- Rosetrees Trust [M145] Funding Source: researchfish
- MRC [MR/K000608/1] Funding Source: UKRI
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Nemaline myopathy (NM) is a rare congenital muscle disorder primarily affecting skeletal muscles that results in neonatal death in severe cases as a result of associated respiratory insufficiency. NM is thought to be a disease of sarcomeric thin filaments as six of eight known genes whose mutation can cause NM encode components of that structure, however, recent discoveries of mutations in non-thin filament genes has called this model in question. We performed whole-exome sequencing and have identified recessive small deletions and missense changes in the Kelch-like family member 41 gene (KLHL41) in four individuals from unrelated NM families. Sanger sequencing of 116 unrelated individuals with NM identified compound heterozygous changes in KLHL41 in a fifth family. Mutations in KLHL41 showed a clear phenotype-genotype correlation: Frameshift mutations resulted in severe phenotypes with neonatal death, whereas missense changes resulted in impaired motor function with survival into late childhood and/or early adulthood. Functional studies in zebrafish showed that loss of Klhl41 results in highly diminished motor function and myofibrillar disorganization, with nemaline body formation, the pathological hallmark of NM. These studies expand the genetic heterogeneity of NM and implicate a critical role of BTB-Kelch family members in maintenance of sarcomeric integrity in NM.
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