Variants in the zinc transporter TMEM163 cause a hypomyelinating leukodystrophy
Variants in the zinc transporter TMEM163 cause a hypomyelinating leukodystrophy
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DOI：
10.1093/brain/awac295
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发表时间：
2022-09-22
期刊：
影响因子：
14.5
通讯作者：
Shukla, Anju
中科院分区：
文献类型：
--
作者：
do Rosario, Michelle C.;Bey, Guillermo Rodriguez;Shukla, Anju
低髓鞘形成脑白质营养不良包括CNS白色物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庭与一个低髓鞘形成脑白质营养不良表型窝藏TMEM 163（NM_030923.5）的变体。最初的临床表现类似于Pelizaeus-Merzbacher病，伴有先天性眼球震颤、肌张力减退、整体发育延迟和神经影像学结果提示显著和弥漫性髓鞘形成不足。基因组检测在TMEM 163中鉴定出三种不同的杂合错义变体，其中两个不相关的个体共享相同的从头变体。TMEM 163在CNS中高度表达，特别是在新生髓鞘少突胶质细胞中，并且最近被揭示作为锌流出转运蛋白发挥作用。所有的变体鉴定在于在蛋白质的胞质结构域中的高度保守的残基，和功能的突变体蛋白质的体外分析表明显着损害的能力，流出锌的细胞。突变蛋白在少突胶质细胞系中的表达导致关键髓鞘基因的mRNA表达显著降低，分支减少和细胞死亡增加。我们的研究结果表明TMEM 163的变异体引起了髓鞘生成不足型脑白质营养不良，并揭示了锌稳态在少突胶质细胞发育和髓鞘中的新作用formation.do罗萨里奥等人鉴定了由锌转运蛋白基因TMEM 163的杂合变异体引起的髓鞘生成不足型脑白质营养不良的新亚型，并揭示了锌稳态在少突胶质细胞发育和髓鞘形成中的作用。
Hypomyelinating leukodystrophies comprise a subclass of genetic disorders with deficient myelination of the 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.do Rosario et al. identify a novel subtype of hypomyelinating leukodystrophy caused by heterozygous variants in the zinc transporter gene TMEM163 and uncover a role for zinc homeostasis in oligodendrocyte development and myelin formation.