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.

中文翻译：

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严重先天性肌无力综合征中的胆碱转运蛋白突变破坏了转运蛋白的定位

突触前高亲和力胆碱转运体是神经递质乙酰胆碱在中枢和外周胆碱能突触（包括神经肌肉接头）信号传导的关键决定因素。在这里，我们描述了一种常染色体隐性遗传的突触前先天性肌无力综合征，由于纯合胆碱转运蛋白错义突变而呈现出广泛的临床表型。临床表型范围从一名患者的典型先天性肌无力综合征 (p.Pro210Leu) 到严重的脑萎缩神经发育迟缓 (p.Ser94Arg)，并将临床结果扩展到更严重的婴儿致死谱 (p. Val112Glu)。用突变转运蛋白构建体转染的细胞显示转运活性几乎完全丧失，同时转运蛋白细胞表面表达减少。与这些发现一致，研究确定基因突变对贩运的影响秀丽隐杆线虫胆碱转运蛋白直系同源物显示转运蛋白输出到轴突和神经末梢的缺陷。这些发现与我们之前在胆碱转运蛋白 C 端显性负移码突变的常染色体显性远端遗传性运动神经病中的发现形成对比，该突变与胆碱转运蛋白功能显着降低但未完全消除有关。我们的研究结果共同定义了由不同类别的胆碱转运蛋白突变引起的不同神经病理学结果，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的乙酰胆碱神经传递中所起的重要作用，对治疗和药物选择具有重要意义。