Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy
Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy
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DOI：
10.1212/wnl.0000000000003595
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发表时间：
2017-02-07
期刊：
影响因子：
9.9
通讯作者：
Jordanova, Albena
中科院分区：
文献类型：
--
作者：
Atkinson, Derek;Glumac, Jelena Nikodinovic;Jordanova, Albena
目的：确定一个轴突型周围神经病变和非典型病程的核心家族的未知遗传原因。方法：对患者进行详细的神经学、电生理和神经病理学检查。完成了两个受影响个体的全外显子组测序。在患者源性淋巴细胞的cDNA和蛋白水平上研究了所鉴定的序列变异的影响。分析等离子体括约肌基底剖面。在果蝇中研究了神经元特异性下调该基因的功能后果。结果：两例患者均表现为不典型的轴突周围神经病变，其特点是急性或亚急性发作和复发性单神经病变。我们在编码鞘氨醇1-磷酸裂解酶（SPL）的SGPL1基因中发现了与疾病共聚的复合杂合突变，而在对照组中不存在。p. Ser361*突变触发非感应介导的mRNA衰变。错义p. Ile184Thr突变导致部分蛋白质降解。患者血浆鞘氨醇1-磷酸水平及鞘氨醇/鞘氨氨酸比值升高。果蝇同源体神经元特异性下调会损害神经肌肉连接处的形态，并导致支配翼缘刚毛的化学感觉神经元进行性变性。结论：我们认为SPL缺乏是人类一种独特形式的腓骨肌肌萎缩症的原因，从而扩展了目前公认的遗传性周围神经病变的临床和遗传谱。我们的数据强调鞘脂代谢对神经元功能的重要性。
Objective: To identify the unknown genetic cause in a nuclear family with an axonal form of peripheral neuropathy and atypical disease course.Methods: Detailed neurologic, electrophysiologic, and neuropathologic examinations of the patients were performed. Whole exome sequencing of both affected individuals was done. The effect of the identified sequence variations was investigated at cDNA and protein level in patient-derived lymphoblasts. The plasma sphingoid base profile was analyzed. Functional consequences of neuron-specific downregulation of the gene were studied in Drosophila.Results: Both patients present an atypical form of axonal peripheral neuropathy, characterized by acute or subacute onset and episodes of recurrent mononeuropathy. We identified compound heterozygous mutations cosegregating with disease and absent in controls in the SGPL1 gene, encoding sphingosine 1-phosphate lyase (SPL). The p. Ser361* mutation triggers nonsensemediated mRNA decay. The missense p. Ile184Thr mutation causes partial protein degradation. The plasma levels of sphingosine 1-phosphate and sphingosine/sphinganine ratio were increased in the patients. Neuron-specific downregulation of the Drosophila orthologue impaired the morphology of the neuromuscular junction and caused progressive degeneration of the chemosensory neurons innervating the wing margin bristles.Conclusions: We suggest SPL deficiency as a cause of a distinct form of Charcot-Marie-Tooth disease in humans, thus extending the currently recognized clinical and genetic spectrum of inherited peripheral neuropathies. Our data emphasize the importance of sphingolipid metabolism for neuronal function.