Biallelic mutation of UNC50, encoding a protein involved in AChR trafficking, is responsible for arthrogryposis.
Hum Mol Genet
; 26(20): 3989-3994, 2017 10 15.
Article
in En
| MEDLINE
| ID: mdl-29016857
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_751delp.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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Arthrogryposis
/
Frameshift Mutation
/
Receptors, Cholinergic
/
RNA-Binding Proteins
/
Membrane Proteins
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Hum Mol Genet
Journal subject:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Year:
2017
Type:
Article
Affiliation country:
France