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: 10.93). 02/2012; 90(3):457-66. DOI: 10.1016/j.ajhg.2012.01.018
Source: PubMed


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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    • "The link between SLC30A10 and Mn levels was also highlighted in a recent genome-wide association study in which genetic variation associated with serum Mn levels was mapped to SLC30A10 (Ng et al., 2015). Moreover, Mn induced up-regulation of SLC30A10 protein in cell culture (Quadri et al., 2012) and expression of human wild-type SLC30A10 in yeast (Saccharomyces cerevisiae) allowed the cells to grow in high-Mn conditions (Tuschl et al., 2012), further supporting the role of SLC30A10 as a key regulator of Mn homeostasis. The SLC30A10 protein, which localizes at the cell surface, protects the cell against toxic Mn levels by functioning as a Mn efflux transporter (Leyva-Illades et al., 2014). "
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    ABSTRACT: Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single-nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes a Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped two SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N=406), the Argentinean Andes (N=198), and Italy (N=238). We also measured SLC30A10 expression in whole blood by TaqMan PCR in a sub-group (N=101) from the Andean cohort, and neurological parameters (sway velocity and finger-tapping speed) in the Italian cohort.The rs2275707 variant allele was associated with increased Mn concentrations in the Andes (8%, p=0.027) and Italy (10.6%, p=0.012), but not as clear in Bangladesh (3.4%, p=0.21; linear regression analysis adjusted for age, gender, and plasma ferritin). This allele was also associated with increased sway velocity (15%, p=0.033; adjusted for age and sex) and reduced SLC30A10 expression (-24.6%, p=0.029). By contrast, the rs12064812 variant homozygous genotype was associated with reduced Mn concentrations, particularly in the Italian cohort (-18.4%, p=0.04), and increased finger-tapping speed (8.7%, p=0.025).We show that common SNPs in SLC30A10 are associated with blood Mn concentrations in three unrelated cohorts and that their influence may be mediated by altered SLC30A10 expression. Moreover, the SNPs appeared to influence neurological functions independent of blood Mn concentrations, suggesting that SLC30A10 could regulate brain Mn levels.
    Full-text · Article · Dec 2015 · Toxicological Sciences
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    • "Those mutation carriers who received levodopa/carbidopa administration were resistant to its beneficial effects on parkinsonism (Quadri et al., 2012), with the exception of one case in which mild improvement was noted at the beginning of the treatment but was not sustained (Stamelou et al., 2012). In regard to differences between the two types of Mn intoxication, the blood Mn levels of SLC30A10 mutation carriers were considerably higher than those described in environmentally exposed individuals (Burkhard et al., 2003; Quadri et al., 2012; Sikk et al., 2010, 2013; Stamelou et al., 2012; Tuschl et al., 2012), and polycythemia and reduced iron levels have only been described in Mn neurotoxicity associated with SLC30A10 mutations (Stamelou et al., 2012) or in cell lines exposed to toxic levels of Mn (DeWitt et al., 2013). Together, these findings support the likelihood that factors other than dopaminergic neuron degeneration in the SNpc are responsible 208 | TOXICOLOGICAL SCIENCES, 2015, Vol. "
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    ABSTRACT: Movement abnormalities caused by chronic manganese (Mn) intoxication clinically resemble but are not identical to those in idiopathic Parkinson's disease. In fact, the most successful parkinsonian drug treatment, the dopamine precursor levodopa, is ineffective in alleviating Mn-induced motor symptoms, implying that parkinsonism in Mn-exposed individuals may not be linked to midbrain dopaminergic neuron cell loss. Over the last decade, supporting evidence from human and nonhuman primates has emerged that Mn-induced parkinsonism partially results from damage to basal ganglia nuclei of the striatal "direct pathway" (ie, the caudate/putamen, internal globus pallidus, and substantia nigra pars reticulata) and a marked inhibition of striatal dopamine release in the absence of nigrostriatal dopamine terminal degeneration. Recent neuroimaging studies have revealed similar findings in a particular group of young drug users intravenously injecting the Mn-containing psychostimulant ephedron and in individuals with inherited mutations of the Mn transporter gene SLC30A10. This review will provide a detailed discussion about the aforementioned studies, followed by a comparison with their rodent analogs and idiopathic parkinsonism. Together, these findings in combination with a limited knowledge about the underlying neuropathology of Mn-induced parkinsonism strongly support the need for a more complete understanding of the neurotoxic effects of Mn on basal ganglia function to uncover the appropriate cellular and molecular therapeutic targets for this disorder. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail:
    Preview · Article · Aug 2015 · Toxicological Sciences
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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.
    Full-text · Article · Aug 2014 · Frontiers in Genetics
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