Mutations of GPR126 Are Responsible for Severe Arthrogryposis Multiplex Congenita
Mutations of GPR126 Are Responsible for Severe Arthrogryposis Multiplex Congenita
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DOI：
10.1016/j.ajhg.2015.04.014
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发表时间：
2015-06-04
影响因子：
9.8
通讯作者：
Laing, Nigel G.
中科院分区：
文献类型：
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作者：
Ravenscroft, Gianina;Nolent, Flora;Laing, Nigel G.
先天性多发性关节挛缩症是指两个或多个主要关节出现挛缩，并由胎动减少或缺乏引起。在这里，我们提出了三个血缘家庭的影响致命的先天性多发性关节挛缩症。通过全外显子组或靶向外显子组测序，结果表明，先证者各自在GPR 126中携带不同的纯合突变（一个错义突变，一个无义突变和一个移码突变）。GPR 126编码G蛋白偶联受体126，其已被证明是鱼类和小鼠外周神经系统中轴突髓鞘形成所必需的。先前的一项研究报道，Gpr 126（-/-）小鼠具有致死性关节弯曲表型。我们已经表明，周围神经在一个家庭的受影响的个人缺乏髓鞘碱性蛋白，这表明这种疾病在受影响的个人是由于有缺陷的髓鞘形成的外周轴突在胎儿发育。先前的工作已经表明，自身蛋白水解切割对于激活GPR 126信号传导是重要的，并且我们的生物化学测定表明错义取代（p.Val769Glu [c.2306T>A]）损害GPR 126的自身蛋白水解切割。我们的数据表明，GPR 126对人类外周神经的髓鞘形成至关重要。这项研究增加了文献暗示有缺陷的轴突功能作为严重的先天性多发性关节弯曲症的一个关键原因，并建议GPR 126突变应在受这种疾病影响的个人进行调查。
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.