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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Identification of KLHL41 mutations implicates BTB-Kelch-mediated ubiquitination as an alternate pathway to myofibrillar disruption in nemaline myopathy
American Journal of Human Genetics, Volume 93, No. 6, Year 2013
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Description
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. © 2013 The American Society of Human Genetics.
Authors & Co-Authors
Gupta, Vandana A.
United States, Boston
Boston Children's Hospital
Ravenscroft, Gina
Australia, Perth
The Harry Perkins Institute of Medical Research
Shaheen, Ranad
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Todd, Emily J.
Australia, Perth
The Harry Perkins Institute of Medical Research
Swanson, Lindsay C.
United States, Boston
Boston Children's Hospital
Shiina, Masaaki
Japan, Yokohama
School of Medicine
Ogata, Kazuhiro
Japan, Yokohama
School of Medicine
Hsu, Cynthia
United States, Boston
Boston Children's Hospital
Clarke, Nigel F.
Australia, Sydney
The University of Sydney
Darras, Basil T.
United States, Boston
Boston Children's Hospital
Farrar, Michelle A.
Australia, Sydney
Sydney Children's Hospital, Randwick
Hashem, Amal Al
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Manton, Nicholas D.
Australia, Adelaide
Women's and Children's Hospital Adelaide
Muntoni, Francesco M.
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
North, Kathryn N.
Australia, Melbourne
Royal Children's Hospital, Melbourne
Sandaradura, Sarah Annabella
Australia, Sydney
The University of Sydney
Nishino, Ichizo
Japan, Kodaira
National Institute of Neuroscience, Kodaira
Hayashi, Yukiko K.
Japan, Kodaira
National Institute of Neuroscience, Kodaira
Sewry, Caroline A.
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Thompson, Elizabeth Mary
Australia, Adelaide
The University of Adelaide
Australia, Adelaide
Women's and Children's Hospital Adelaide
Yau, Kyle S.Y.
Australia, Perth
The Harry Perkins Institute of Medical Research
Brownstein, Catherine A.
United States, Boston
Boston Children's Hospital
Yu, Timothy W.
United States, Boston
Boston Children's Hospital
Allcock, Richard James Nigel
Australia, Perth
The University of Western Australia
Davis, Mark R.
Australia, Perth
Royal Perth Hospital
Wallgren-Pettersson, Carina
Finland, Helsinki
Helsingin Yliopisto
Matsumoto, Naomichi
Japan, Yokohama
School of Medicine
Alkuraya., Fowzan S.
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Laing, Nigel G.
Australia, Perth
The Harry Perkins Institute of Medical Research
Beggs, Alan H.
United States, Boston
Boston Children's Hospital
Statistics
Citations: 150
Authors: 30
Affiliations: 14
Identifiers
Doi:
10.1016/j.ajhg.2013.10.020
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Cancer
Genetics And Genomics
Maternal And Child Health