Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization
Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization
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DOI：
10.1093/brain/awx249
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发表时间：
2017-11-01
期刊：
影响因子：
14.5
通讯作者：
Crosby, Andrew H.
中科院分区：
文献类型：
--
作者：
Wang, Haicui;Salter, Claire G.;Crosby, Andrew H.
突触前高亲和力胆碱转运蛋白是中枢和外周胆碱能突触（包括神经肌肉接头）神经递质乙酰胆碱信号传导的关键决定因素。在这里，我们描述了一个常染色体隐性遗传性突触前先天性肌无力综合征提出了广泛的临床表型，由于纯合子胆碱转运蛋白错义突变。临床表型的范围从1例患者的先天性肌无力综合征的经典表现（p.Pro210Leu）到伴有脑萎缩的严重神经发育迟缓（p.Ser94Arg），并将临床结局扩展到更严重的婴儿致死性（p.Val112Glu）。用突变体转运蛋白构建体转染的细胞显示转运活性几乎完全丧失，这是由于转运蛋白细胞表面表达减少所致。与这些发现一致，确定基因突变对秀丽隐杆线虫胆碱转运蛋白直系同源物贩运的影响的研究显示，转运蛋白向轴突和神经末梢的出口存在缺陷。这些发现与我们以前在常染色体显性遗传性远端遗传性运动神经病中发现的胆碱转运蛋白C端显性负移码突变形成对比，该突变与胆碱转运蛋白功能显著降低相关，但未完全消除。我们的研究结果共同定义了不同类型的胆碱转运蛋白突变所产生的不同的神经病理学结果，这些突变具有不同的疾病过程和遗传模式。这些发现强调了胆碱转运蛋白在维持中枢和神经肌肉突触乙酰胆碱神经传递中的重要作用，对治疗和药物选择具有重要意义。
The presynaptic, high-affinity choline transporter is a critical determinant of signalling by the neurotransmitter acetylcholine at both central and peripheral cholinergic synapses, including the neuromuscular junction. Here we describe an autosomal recessive presynaptic congenital myasthenic syndrome presenting with a broad clinical phenotype due to homozygous choline transporter missense mutations. The clinical phenotype ranges from the classical presentation of a congenital myasthenic syndrome in one patient (p.Pro210Leu), to severe neurodevelopmental delay with brain atrophy (p.Ser94Arg) and extend the clinical outcomes to a more severe spectrum with infantile lethality (p.Val112Glu). Cells transfected with mutant transporter construct revealed a virtually complete loss of transport activity that was paralleled by a reduction in transporter cell surface expression. Consistent with these findings, studies to determine the impact of gene mutations on the trafficking of the Caenorhabditis elegans choline transporter orthologue revealed deficits in transporter export to axons and nerve terminals. These findings contrast with our previous findings in autosomal dominant distal hereditary motor neuropathy of a dominant-negative frameshift mutation at the C-terminus of choline transporter that was associated with significantly reduced, but not completely abrogated choline transporter function. Together our findings define divergent neuropathological outcomes arising from different classes of choline transporter mutation with distinct disease processes and modes of inheritance. These findings underscore the essential role played by the choline transporter in sustaining acetylcholine neurotransmission at both central and neuromuscular synapses, with important implications for treatment and drug selection.