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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Animals
  • Arthrogryposis / genetics*
  • Arthrogryposis / metabolism*
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics
  • Disease Models, Animal
  • Female
  • Frameshift Mutation*
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Neuromuscular Junction / genetics
  • Neuromuscular Junction / metabolism
  • Pedigree
  • Protein Transport
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism*
  • Receptors, Cholinergic / genetics
  • Receptors, Cholinergic / metabolism*
  • Stillbirth / genetics


  • Caenorhabditis elegans Proteins
  • Membrane Proteins
  • RNA-Binding Proteins
  • Receptors, Cholinergic
  • UNC50 protein, human