SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation
SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation
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DOI：
10.1016/j.ajhg.2015.11.003
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发表时间：
2015-12-01
影响因子：
9.8
通讯作者：
Marquardt, Thorsten
中科院分区：
文献类型：
--
作者：
Park, Julien H.;Hogrebe, Max;Marquardt, Thorsten
SLC39A8是一种膜转运蛋白，负责将锰吸收到细胞中。通过全外显子组测序，我们研究了一个表现为颅骨不对称、严重婴儿痉挛伴心律失常和不成比例侏儒症的儿童。转铁蛋白糖基化分析显示严重的糖基化异常，对应于II型先天性糖基化障碍（CDG），血锰水平低于检测限。在SLC39A8中鉴定出C . 112g >C （p.Gly38Arg）和C . 1019t >A （p.Ile340Asn）变体。在一组未解决的CDG病例中，鉴定出第二例在父本等位基因上携带C . 97g >A （p.Val33Met）和C . 1004g >C （p.Ser335Thr）变异，在母本等位基因上携带C . 610g >T （p.p el204cys）变异的个体。这些数据表明，SLC39A8的变异损害了锰依赖酶的功能，尤其是β -1,4-半乳糖转移酶，这是一种高尔基酶，对糖蛋白的碳水化合物部分的生物合成至关重要。半乳糖基化受损会导致严重的疾病，包括颅骨畸形、严重癫痫发作、四肢短促、严重精神运动迟缓和听力丧失。口服半乳糖补充是一种治疗选择，可使糖基化完全正常化。SLC39A8缺乏将微量元素缺乏与遗传性糖基化疾病联系起来。
SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably beta-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders.