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Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man

Clinical and Molecular Genetics Unit, University College London Institute of Child Health, UK.
The American Journal of Human Genetics (Impact Factor: 10.99). 02/2012; 90(3):457-66. DOI: 10.1016/j.ajhg.2012.01.018
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ABSTRACT 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 identified SLC30A10 as 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 strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast 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 in SLC30A10 failed 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.

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    • "SLC30A10 is localized at the cell membrane, and mutations in this gene either result in early truncation of this protein or amino acid substitution (Quadri et al., 2012; Stamelou et al., 2012; Tuschl et al., 2012). Interestingly , none of the patients were exposed to excessive Mn, yet they displayed symptoms consistent with PD (Quadri et al., 2012; Stamelou et al., 2012; Tuschl et al., 2012). SLC30A10 is the only protein known to cause Mn toxicity when mutated, indicating it may be a primary and a key regulator of Mn export. "
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    ABSTRACT: Manganese (Mn), is a trace metal required for normal physiological processes in humans. Mn levels are tightly regulated, as high levels of Mn result in accumulation in the brain and cause a neurological disease known as manganism. Manganism shares many similarities with Parkinson's disease (PD), both at the physiological level and the cellular level. Exposure to high Mn-containing environments increases the risk of developing manganism. Mn is absorbed primarily through the intestine and then released in the blood. Excessive Mn is secreted in the bile and excreted in feces. Mn enters and exits cells through a number of non-specific importers localized on the cell membrane. Mutations in one of the Mn exporters, SLC30A10 (solute carrier family 30, member 10), result in Mn induced toxicity with liver impairments and neurological dysfunction. Four PD genes have been identified in connection to regulation of Mn toxicity, shedding new light on potential links between manganism and PD.
    Frontiers in Genetics 08/2014; 5:265. DOI:10.3389/fgene.2014.00265
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    • "However, another group reported that ZnT10 localizes in endosomes of smooth muscle cells (Patrushev et al. 2012). Notably, mutations in ZnT10 gene have been associated with liver cirrhosis, dystonia, polycythemia, and hypermanganesemia (Tuschl et al. 2012). Lastly, the expression of ZnT10 has been found to be downregulated in brain of subjects with Alzheimer's disease (Bosomworth et al. 2013), a condition that has been shown to be associated with defective autophagy (Orr and Oddo 2013; Nilsson and Saido 2014). "
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    • "Other studies reported that down regulation of ZnT-3 and ZnT-10 can result in early senescence and cardiovascular diseases [11]. The syndromes of hepatic cirrhosis, dystonia, polycythemia, Parkinsonism, chronic liver disease and hypermanganesemia were found to be caused by mutations in ZnT-10 [12], [13]. In addition, increased risk of developing Type-II diabetes is associated with single amino acid polymorphisms of the human ZnT-8 [14]. "
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