鞘氨醇-1-磷酸裂解酶缺乏会导致夏科-马里-图斯神经病变。
Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy.
作者信息
Atkinson Derek, Nikodinovic Glumac Jelena, Asselbergh Bob, Ermanoska Biljana, Blocquel David, Steiner Regula, Estrada-Cuzcano Alejandro, Peeters Kristien, Ooms Tinne, De Vriendt Els, Yang Xiang-Lei, Hornemann Thorsten, Milic Rasic Vedrana, Jordanova Albena
机构信息
From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
出版信息
Neurology. 2017 Feb 7;88(6):533-542. doi: 10.1212/WNL.0000000000003595. Epub 2017 Jan 11.
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 nonsense-mediated 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.
目的
在一个患有轴索性周围神经病且病程不典型的核心家庭中确定未知的遗传病因。
方法
对患者进行了详细的神经学、电生理学和神经病理学检查。对两名受累个体进行了全外显子组测序。在患者来源的淋巴母细胞中，从cDNA和蛋白质水平研究了所鉴定序列变异的影响。分析了血浆鞘氨醇碱基谱。在果蝇中研究了该基因神经元特异性下调的功能后果。
结果
两名患者均表现为轴索性周围神经病的非典型形式，其特征为急性或亚急性起病以及复发性单神经病发作。我们在编码鞘氨醇-1-磷酸裂解酶（SPL）的SGPL1基因中鉴定出与疾病共分离且在对照中不存在的复合杂合突变。p.Ser361*突变触发无义介导的mRNA降解。错义p.Ile184Thr突变导致部分蛋白质降解。患者血浆中鞘氨醇-1-磷酸水平和鞘氨醇/二氢鞘氨醇比值升高。果蝇同源基因的神经元特异性下调损害了神经肌肉接头的形态，并导致支配翅缘刚毛的化学感觉神经元进行性退化。
结论
我们认为SPL缺乏是人类一种独特形式的夏科-马里-图斯病的病因，从而扩展了目前公认的遗传性周围神经病的临床和遗传谱。我们的数据强调了鞘脂代谢对神经元功能的重要性。
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