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Hum Mol Genet. 2017 Oct 15;26(20):3989-3994. doi: 10.1093/hmg/ddx288.

Biallelic mutation of UNC50, encoding a protein involved in AChR trafficking, is responsible for arthrogryposis.

Author information

1
Institut National de la Santé et de la Recherche Médicale (Inserm) UMR-1169, Université Paris Sud, 94276 Le Kremlin Bicêtre, France.
2
INSERM U-1217, Institut NeuroMyoGène, Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5310, F-69622 Villeurbanne, France.
3
Unité de Génétique Clinique, Département de Génétique et Procréation, CHU Grenoble, 38043 Grenoble, France.
4
Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble, 38043 Grenoble, France.
5
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Universitat Pompeu Fabra (UPF), 08028 Barcelona, Spain.
6
Hospices Civils de Lyon, 69500 Lyon, Bron.

Abstract

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Homozygosity mapping of disease loci combined with whole exome sequencing in a consanguineous family presenting with lethal AMC allowed the identification of a homozygous frameshift deletion in UNC50 gene (c.750_751del:p.Cys251Phefs*4) in the index case. To assess the effect of the mutation, an equivalent mutation in the Caenorhabditis elegans orthologous gene was created using CRISPR/Cas9. We demonstrated that unc-50(kr331) modification caused the loss of acetylcholine receptor (AChR) expression in C. elegans muscle. unc-50(kr331) animals were as resistant to the cholinergic agonist levamisole as unc-50 null mutants suggesting that AChRs were no longer expressed in this animal model. This was confirmed by using a knock-in strain in which a red fluorescent protein was inserted into the AChR locus: no signal was detected in unc-50(kr331) background, suggesting that UNC-50, a protein known to be involved in AChR trafficking, was no longer functional. These data indicate that biallelic mutation in the UNC50 gene underlies AMC through a probable loss of AChR expression at the neuromuscular junction which is essential for the cholinergic transmission during human muscle development.

PMID:
29016857
DOI:
10.1093/hmg/ddx288
[Indexed for MEDLINE]

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