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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.

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


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.

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