Mutations in SLC30A10 Cause Parkinsonism and Dystonia with Hypermanganesemia, Polycythemia, and Chronic Liver Disease
Mutations in SLC30A10 Cause Parkinsonism and Dystonia with Hypermanganesemia, Polycythemia, and Chronic Liver Disease
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DOI：
10.1016/j.ajhg.2012.01.017
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发表时间：
2012-03-09
影响因子：
9.8
通讯作者：
Bonifati, Vincenzo
中科院分区：
文献类型：
--
作者：
Quadri, Marialuisa;Federico, Antonio;Bonifati, Vincenzo
锰是几种代谢途径所必需的，但过量会变得有毒。因此，人体内的锰水平受到严格控制，但负责的蛋白质仍不完全清楚。我们研究了两个有神经系统疾病的近亲家族，包括青少年发作的肌张力障碍，成年发作的帕金森综合征，严重的高锰血症，红细胞增多症，和慢性肝病，包括脂肪变性和肝硬化。我们通过纯合性作图定位了遗传缺陷，然后鉴定了两种不同的纯合移码突变SLC30A10，与疾病分离。SLC30A10在肝脏和大脑中高度表达，包括基底神经节。其编码的蛋白质属于膜转运蛋白的大家族，介导二价阳离子从胞质溶胶的流出。我们显示了SLC30A10在正常人肝脏和神经系统中的定位，以及其在一个受影响个体的肝脏中的耗尽。我们的计算机分析表明，SLC30A10具有底物特异性不同于其最接近的（锌转运）同系物。我们还表明，SLC30A10的表达和编码的蛋白质的水平显着诱导锰在体外。与SLC30A10突变相关的表型广泛，包括神经系统、肝脏和血液系统紊乱。家族内表型变异也存在。螯合疗法可以使锰血症正常化，从而导致显著的临床改善。总之，我们表明，SLC30A10突变导致一种可治疗的隐性疾病与多形性表型，并提供令人信服的证据表明，SLC30A10在锰的运输中起着关键作用。这项工作具有广泛的意义，了解锰的生物学和病理生理学在多个人体器官。
Manganese is essential for several metabolic pathways but becomes toxic in excessive amounts. Manganese levels in the body are therefore tightly regulated, but the responsible protein(s) remain incompletely known. We studied two consanguineous families with neurologic disorders including juvenile-onset dystonia, adult-onset parkinsonism, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis. We localized the genetic defect by homozygosity mapping and then identified two different homozygous frameshift SLC30A10 mutations, segregating with disease. SLC30A10 is highly expressed in the liver and brain, including in the basal ganglia. Its encoded protein belongs to a large family of membrane transporters, mediating the efflux of divalent cations from the cytosol. We show the localization of SLC30A10 in normal human liver and nervous system, and its depletion in liver from one affected individual. Our in silico analyses suggest that SLC30A10 possesses substrate specificity different from its closest (zinc-transporting) homologs. We also show that the expression of SLC30A10 and the levels of the encoded protein are markedly induced by manganese in vitro. The phenotype associated with SLC30A10 mutations is broad, including neurologic, hepatic, and hematologic disturbances. Intrafamilial phenotypic variability is also present. Chelation therapy can normalize the manganesemia, leading to marked clinical improvements. In conclusion, we show that SLC30A10 mutations cause a treatable recessive disease with pleomorphic phenotype, and provide compelling evidence that SLC30A10 plays a pivotal role in manganese transport. This work has broad implications for understanding of the manganese biology and pathophysiology in multiple human organs.