Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita

Am J Hum Genet. 2015 Jun 4;96(6):955-61. doi: 10.1016/j.ajhg.2015.04.014.

Gianina Ravenscroft ¹, Flora Nolent ², Sulekha Rajagopalan ³, Ana M Meireles ⁴, Kevin J Paavola ⁴, Dominique Gaillard ⁵, Elisabeth Alanio ⁶, Michael Buckland ⁷, Susan Arbuckle ⁸, Michael Krivanek ⁸, Jérome Maluenda ², Stephen Pannell ¹, Rebecca Gooding ⁹, Royston W Ong ¹, Richard J Allcock ¹⁰, Ellaine D F Carvalho ¹¹, Maria D F Carvalho ¹², Fernando Kok ¹³, William S Talbot ⁴, Judith Melki ¹⁴, Nigel G Laing ¹⁵

Affiliations

1 Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia.
2 Unité Mixte de Recherche-1169, INSERM, le Kremlin-Bicêtre 94276, France; University Paris-Sud, le Kremlin-Bicêtre 94276, France.
3 Department of Clinical Genetics, Liverpool Hospital, Liverpool, NSW 1871, Australia.
4 Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
5 Genetics Department, Maison Blanche Hospital, Centre Hospitalier Universitaire de Reims, Reims 51092, France.
6 Pol Bouin Laboratory, University Hospital, Reims 51092, France.
7 Brain & Mind Research Institute, University of Sydney, Sydney, NSW 2006, Australia; Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
8 Department of Pathology, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia.
9 Department of Diagnostic Genomics, PathWest Laboratory Medicine, Nedlands, WA 6009, Australia.
10 Lotterywest State Biomedical Facility Genomics, School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA 6009, Australia.
11 Christus University Center, Fortaleza, CE, 04013-000, Brazil; Genpharma Consultoria Farmaceutica e Genetica, Ltda, Fortaleza, CE 60160-230, Brazil.
12 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.
13 Mendelics Genomic Analysis, Sao Paulo, SP 04013-000, Brazil.
14 Unité Mixte de Recherche-1169, INSERM, le Kremlin-Bicêtre 94276, France; University Paris-Sud, le Kremlin-Bicêtre 94276, France. Electronic address: [email protected].
15 Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA 6009, Australia. Electronic address: [email protected].

PMID: 26004201 DOI: 10.1016/j.ajhg.2015.04.014

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.

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