Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita.

Abstract

Arthrogryposis multiplex congenita is defined by the presence of contractures across two or more major joints and results from reduced or absent fetal movement. Here, we present three consanguineous families affected by lethal arthrogryposis multiplex congenita. By whole-exome or targeted exome sequencing, it was shown that the probands each harbored a different homozygous mutation (one missense, one nonsense, and one frameshift mutation) in GPR126. GPR126 encodes G-protein-coupled receptor 126, which has been shown to be essential for myelination of axons in the peripheral nervous system in fish and mice. A previous study reported that Gpr126(-/-) mice have a lethal arthrogryposis phenotype. We have shown that the peripheral nerves in affected individuals from one family lack myelin basic protein, suggesting that this disease in affected individuals is due to defective myelination of the peripheral axons during fetal development. Previous work has suggested that autoproteolytic cleavage is important for activating GPR126 signaling, and our biochemical assays indicated that the missense substitution (p.Val769Glu [c.2306T>A]) impairs autoproteolytic cleavage of GPR126. Our data indicate that GPR126 is critical for myelination of peripheral nerves in humans. This study adds to the literature implicating defective axoglial function as a key cause of severe arthrogryposis multiplex congenita and suggests that GPR126 mutations should be investigated in individuals affected by this disorder.

• Authors: Gianina Ravenscroft, Flora Nolent, Sulekha Rajagopalan, Ana M Meireles, Kevin J Paavola, Dominique Gaillard, Elisabeth Alanio, Michael Buckland, Susan Arbuckle, Michael Krivanek, Jérome Maluenda, Stephen Pannell, Rebecca Gooding, Royston W Ong, Richard J Allcock, Ellaine D F Carvalho, Maria D F Carvalho, Fernando Kok, William S Talbot, Judith Melki, Nigel G Laing
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 96 Issue 6 Pg. 955-61 (Jun 04 2015) ISSN: 1537-6605 [Electronic] United States
• PMID: 26004201 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• ADGRG6 protein, human
• Receptors, G-Protein-Coupled

Topics

• Amino Acid Sequence
• Arthrogryposis (genetics, pathology)
• Base Sequence
• Exome (genetics)
• Humans
• Immunohistochemistry
• Molecular Sequence Data
• Mutation, Missense (genetics)
• Nerve Fibers, Myelinated (pathology)
• Pedigree
• Receptors, G-Protein-Coupled (genetics)
• Sequence Alignment
• Sequence Analysis, DNA