Loss-of-Function Alanyl-tRNA Synthetase Mutations Cause an Autosomal-Recessive Early-Onset Epileptic Encephalopathy with Persistent Myelination Defect
Loss-of-Function Alanyl-tRNA Synthetase Mutations Cause an Autosomal-Recessive Early-Onset Epileptic Encephalopathy with Persistent Myelination Defect
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DOI：
10.1016/j.ajhg.2015.02.012
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发表时间：
2015-04-02
影响因子：
9.8
通讯作者：
Vanderver, Adeline
中科院分区：
文献类型：
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作者：
Simons, Cas;Griffin, Laurie B.;Vanderver, Adeline
已知编码氨酰-tRNA合成酶的基因突变会引起脑白质营养不良和遗传性脑白质病-导致中枢神经系统中白色物质异常的可遗传疾病。在这里，我们报告三个人（两个兄弟姐妹和一个无关的个人）与严重的婴儿癫痫性脑病，马蹄内翻足，缺乏深腱反射，锥体外系症状，并持续缺乏髓鞘形成的MRI。通过全外显子组测序分析，在这两个不相关的家族中鉴定了核编码的丙氨酰-tRNA合成酶（阿尔斯）的突变：两个受累的兄弟姐妹是p.Lys81Thr和p.Arg751Gly阿尔斯的复合杂合子，而单个受累的孩子是p.Arg751Gly阿尔斯的纯合子。发现这两个鉴定的突变导致功能显著降低。阿尔斯突变以前与常染色体显性遗传形式的轴突神经病，腓骨肌萎缩症2型N（CMT 2 N）。然而，在这里描述的个体中鉴定的常染色体隐性阿尔斯突变引起严重的婴儿癫痫性脑病，伴有中央髓鞘缺陷和周围神经病变，表明丙氨酰-tRNA充电缺陷可导致广泛的疾病表现。
Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations.