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.

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

“…In patient BAB6212, we identified a homozygous stop-gain mutation in GPR126, which was recently reported as a novel gene in 3 families with arthrogryposis (29). However, in this patient, WES data also revealed compound heterozygous variants in another novel gene, MYBPC2 ( Figure 4A).…”

“…A list of known genes (Supplemental Table 1) was constructed from multiple online database resources (http:// www.omim.org/, http://www.mnglabs.com/tests/, http://www. ncbi.nlm.nih.gov/pubmed) or abstracted from recently published articles (2,3,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Deleterious variants in the known arthrogryposis-associated genes were identified in 17 of 48 (35.4%) unrelated families (Table 1).…”

Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy

“…5 Recently, variants in GPR126 were reported in patients with lethal congenital contracture syndrome and lack of myelin basic protein. 6 Homozygous frameshift variants in CNTNAP1 (Contactin-associated protein 1) have been identified in seven patients with arthrogryposis and abnormal axon myelination, considered as lethal congenital contracture syndrome (MIM#616286). 7 CNTNAP1 encodes Caspr that is essential to the paranodal junctions.…”

Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita

“…Therefore, the biallelic mutations found in the affected individuals of these four families are likely to cause defective signaling of the LGI4 pathway similar to that observed in Lgi4-deficient mice. Recent data indicate that mutations of genes encoding CASPR-1 19 and gliomedin, 20 essential components of the nodes of Ranvier and paranodes, respectively, or proteins involved in myelination of Schwann cells such as ADCY6 19 and GPR126, 21 are responsible for severe human peripheral axoglial diseases, resulting in developmental defect of PNS, hypokinesia, and arthrogryposis. Here, we show that loss-of-function germline mutations of LGI4 leads to a similar phenotype.…”