Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man.
Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man.
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肝肝硬化，肌张力障碍，多性性心血症和高镁血症的综合征是由人类中的锰转运蛋白突变引起的。
DOI：
10.1016/j.ajhg.2016.07.015
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发表时间：
2016-08-04
影响因子：
9.8
通讯作者：
Mills PB
中科院分区：
文献类型：
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作者：
Tuschl K;Clayton PT;Gospe SM Jr;Gulab S;Ibrahim S;Singhi P;Aulakh R;Ribeiro RT;Barsottini OG;Zaki MS;Del Rosario ML;Dyack S;Price V;Rideout A;Gordon K;Wevers RA;Chong WK;Mills PB
环境中的锰中毒导致锥体外型帕金森型运动障碍，其核磁共振图像显示基底节中锰的聚集。我们最近报告了一例疑似常染色体隐性遗传综合征，在没有环境锰暴露的病例中出现了肝硬变、肌张力障碍、红细胞增多症和高锰酸血症。两个血缘关系家系的全基因组图谱确定SLC30A10是这种遗传型高锰酸血症的致病基因。随后在8个家系中对该基因进行了测序，并在所有受影响的个体中发现了纯合子序列变化。研究了该野生型蛋白在锰敏感酵母菌株ΔPMr1中的功能及序列改变的影响。在Δpmr1酵母中表达人野生型SLC30A10后，在高锰条件下恢复了生长，证实了其在锰运输中的作用。SLC30A10中存在错义突变(c.266T>；C[p.Leu89Pro])和无义突变(c.585del[p.196Pros∗17])，未能恢复对锰的抗性。此前，SLC30A10曾被推定为锌的转运体。然而，这项工作证实了SLC30A10在人类中作为一种锰转运蛋白的功能，当缺陷时，会导致锰在肝脏和大脑中积累。这是了解锰转运及其在神经退行性变过程中的作用的重要一步。
Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identifiedSLC30A10as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strainΔpmr1. Expressing human wild-typeSLC30A10in theΔpmr1yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs∗17]) mutations inSLC30A10failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes.