PUBLICATION

Identification of KLHL41 Mutations Implicates BTB-Kelch-Mediated Ubiquitination as an Alternate Pathway to Myofibrillar Disruption in Nemaline Myopathy

Authors
Gupta, V.A., Ravenscroft, G., Shaheen, R., Todd, E.J., Swanson, L.C., Shiina, M., Ogata, K., Hsu, C., Clarke, N.F., Darras, B.T., Farrar, M.A., Hashem, A., Manton, N.D., Muntoni, F., North, K.N., Sandaradura, S.A., Nishino, I., Hayashi, Y.K., Sewry, C.A., Thompson, E.M., Yau, K.S., Brownstein, C.A., Yu, T.W., Allcock, R.J., Davis, M.R., Wallgren-Pettersson, C., Matsumoto, N., Alkuraya, F.S., Laing, N.G., and Beggs, A.H.
ID
ZDB-PUB-140108-11
Date
2013
Source
American journal of human genetics   93(6): 1108-1117 (Journal)
Registered Authors
Beggs, Alan H., Gupta, Vandana A
Keywords
none
MeSH Terms
  • Adolescent
  • Animals
  • Child
  • Child, Preschool
  • Fatal Outcome
  • Female
  • Gene Expression
  • Gene Order
  • Genetic Association Studies
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Models, Molecular
  • Muscle, Skeletal/metabolism
  • Muscle, Skeletal/pathology
  • Muscle, Skeletal/ultrastructure
  • Mutation*
  • Myofibrils/metabolism*
  • Myopathies, Nemaline/diagnosis
  • Myopathies, Nemaline/genetics*
  • Myopathies, Nemaline/metabolism*
  • Protein Conformation
  • Protein Interaction Domains and Motifs*
  • Proteins/chemistry
  • Proteins/genetics*
  • Signal Transduction*
  • Ubiquitination*
  • Zebrafish
PubMed
24268659 Full text @ Am. J. Hum. Genet.
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.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping