Hypomyelinating leukodystrophies comprise a subclass of genetic disorders with deficient myelination of the central nervous system (CNS) white matter. Here we report four unrelated families with a hypomyelinating leukodystrophy phenotype harbouring variants in TMEM163 (NM_030923.5). The initial clinical presentation resembled Pelizaeus-Merzbacher disease with congenital nystagmus, hypotonia, delayed global development and neuroimaging findings suggestive of significant and diffuse hypomyelination. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant. TMEM163 is highly expressed in the CNS particularly in newly myelinating oligodendrocytes and was recently revealed to function as a zinc efflux transporter. All the variants identified lie in highly conserved residues in the cytoplasmic domain of the protein, and functional in vitro analysis of the mutant protein demonstrated significant impairment in the ability to efflux zinc out of the cell. Expression of the mutant proteins in an oligodendroglial cell line resulted in substantially reduced mRNA expression of key myelin genes, reduced branching and increased cell death. Our findings indicate that variants in TMEM163 cause a hypomyelinating leukodystrophy and uncover a novel role for zinc homeostasis in oligodendrocyte development and myelin formation.

中文翻译：

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锌转运蛋白 TMEM163 的变异导致低髓鞘性脑白质营养不良

低髓鞘性脑白质营养不良包括中枢神经系统（CNS）白质髓鞘形成缺陷的遗传性疾病的一个亚类。在这里，我们报告了四个不相关的家族，它们具有髓鞘形成不足的脑白质营养不良表型，携带 TMEM163 (NM_030923.5) 变异。最初的临床表现类似于 Pelizaeus-Merzbacher 病，伴有先天性眼球震颤、肌张力低下、整体发育迟缓，神经影像学检查结果提示存在明显的弥漫性髓鞘形成不足。基因组测试在 TMEM163 中发现了三个不同的杂合错义变异，其中两个不相关的个​​体共享相同的从头变异。TMEM163 在中枢神经系统中高度表达，特别是在新形成髓鞘的少突胶质细胞中，并且最近被发现具有锌外流转运蛋白的功能。鉴定出的所有变体都位于蛋白质胞质结构域中高度保守的残基中，对突变蛋白的功能性体外分析表明，锌流出细胞的能力显着受损。突变蛋白在少突胶质细胞系中的表达导致关键髓磷脂基因的 mRNA 表达大幅降低、分支减少和细胞死亡增加。我们的研究结果表明，TMEM163 的变异会导致髓鞘形成不足的脑白质营养不良，并揭示了锌稳态在少突胶质细胞发育和髓磷脂形成中的新作用。