Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/88443
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Type: Journal article
Title: Identification Of KLHL41 mutations implicates BTB-Kelch-Mediated Ubiquitination as an alternate pathway to myofibrillar disruption in nemaline myopathy
Author: Gupta, V.
Ravenscroft, G.
Shaheen, R.
Todd, E.
Swanson, L.
Shiina, M.
Ogata, K.
Hsu, C.
Clarke, N.
Darras, B.
Farrar, M.
Hashem, A.
Manton, N.
Muntoni, F.
North, K.
Sandaradura, S.
Nishino, I.
Hayashi, Y.
Sewry, C.
Thompson, E.
et al.
Citation: American Journal of Human Genetics, 2013; 93(6):1108-1117
Publisher: University of Chicago Press
Issue Date: 2013
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
Vandana A. Gupta, Gianina Ravenscroft, Ranad Shaheen, Emily J. Todd, Lindsay C. Swanson, Masaaki Shiina, Kazuhiro Ogata, Cynthia Hsu, Nigel F. Clarke, Basil T. Darras, Michelle A. Farrar, Amal Hashem, Nicholas D. Manton, Francesco Muntoni, Kathryn N. North, Sarah A. Sandaradura, Ichizo Nishino, Yukiko K. Hayashi, Caroline A. Sewry, Elizabeth M. Thompson, Kyle S. Yau, Catherine A. Brownstein, Timothy W. Yu, Richard J.N. Allcock, Mark R. Davis, Carina Wallgren-Pettersson, Naomichi Matsumoto, Fowzan S. Alkuraya, Nigel G. Laing, and Alan H. Beggs
Abstract: 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.
Keywords: Myofibrils; Muscle, Skeletal; Animals; Zebrafish; Humans; Myopathies, Nemaline; Proteins; Fatal Outcome; Signal Transduction; Gene Expression; Protein Conformation; Gene Order; Mutation; Models, Molecular; Adolescent; Child; Child, Preschool; Infant; Infant, Newborn; Female; Male; Protein Interaction Domains and Motifs; Ubiquitination; Genetic Association Studies
Rights: 2013 by The American Society of Human Genetics. All rights reserved.
RMID: 0020134333
DOI: 10.1016/j.ajhg.2013.10.020
Appears in Collections:Medical Sciences publications

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