title: 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.affiliation: Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia.
authors.forename: Gianina
authors.initials: G
authors.lastname: Ravenscroft
authors.affiliation: Unité Mixte de Recherche-1169, INSERM, le Kremlin-Bicêtre 94276, France; University Paris-Sud, le Kremlin-Bicêtre 94276, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Nolent
authors.affiliation: Department of Clinical Genetics, Liverpool Hospital, Liverpool, NSW 1871, Australia.
authors.forename: Sulekha
authors.initials: S
authors.lastname: Rajagopalan
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Meireles
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Paavola
authors.affiliation: Genetics Department, Maison Blanche Hospital, Centre Hospitalier Universitaire de Reims, Reims 51092, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Gaillard
authors.affiliation: Pol Bouin Laboratory, University Hospital, Reims 51092, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Alanio
authors.affiliation: Brain & Mind Research Institute, University of Sydney, Sydney, NSW 2006, Australia; Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Buckland
authors.affiliation: Department of Pathology, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Arbuckle
authors.affiliation: Department of Pathology, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Krivanek
authors.affiliation: Unité Mixte de Recherche-1169, INSERM, le Kremlin-Bicêtre 94276, France; University Paris-Sud, le Kremlin-Bicêtre 94276, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Maluenda
authors.affiliation: Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Pannell
authors.affiliation: Department of Diagnostic Genomics, PathWest Laboratory Medicine, Nedlands, WA 6009, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gooding
authors.affiliation: Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia.
authors.forename: Royston W
authors.initials: RW
authors.lastname: Ong
authors.affiliation: Lotterywest State Biomedical Facility Genomics, School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA 6009, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Allcock
authors.affiliation: Christus University Center, Fortaleza, CE, 04013-000, Brazil; Genpharma Consultoria Farmaceutica e Genetica, Ltda, Fortaleza, CE 60160-230, Brazil.
authors.forename: Ellaine D F
authors.initials: ED
authors.lastname: Carvalho
authors.affiliation: Christus University Center, Fortaleza, CE, 04013-000, Brazil; Genpharma Consultoria Farmaceutica e Genetica, Ltda, Fortaleza, CE 60160-230, Brazil; Ceará State University, Fortaleza, CE 04013-000, Brazil.
authors.forename: Maria D F
authors.initials: MD
authors.lastname: Carvalho
authors.affiliation: Mendelics Genomic Analysis, Sao Paulo, SP 04013-000, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Talbot
authors.affiliation: Unité Mixte de Recherche-1169, INSERM, le Kremlin-Bicêtre 94276, France; University Paris-Sud, le Kremlin-Bicêtre 94276, France. Electronic address: judith.melki@inserm.fr.
authors.forename: Judith
authors.initials: J
authors.lastname: Melki
authors.affiliation: Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia. Electronic address: nigel.laing@perkins.uwa.edu.au.
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
mesh_terms: D000595:Amino Acid Sequence; D001176:Arthrogryposis / Q000235:genetics* / Q000473:pathology*; D001483:Base Sequence; D059472:Exome / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D010375:Pedigree; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: C488660:ADGRG6 protein, human; D043562:Receptors, G-Protein-Coupled