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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    • "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:
    Toxicological Sciences 08/2015; 146(2):204-12. DOI:10.1093/toxsci/kfv099 · 3.85 Impact Factor
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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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    ABSTRACT: Autophagy is a highly conserved degradative process through which cells overcome stressful conditions. Inasmuch as faulty autophagy has been associated with aging, neuronal degeneration disorders, diabetes, and fatty liver, autophagy is regarded as a potential therapeutic target. This review summarizes the present state of knowledge concerning the role of zinc in the regulation of autophagy, the role of autophagy in zinc metabolism, and the potential role of autophagy as a mediator of the protective effects of zinc. Data from in vitro studies consistently support the notion that zinc is critical for early and late autophagy. Studies have shown inhibition of early and late autophagy in cells cultured in medium treated with zinc chelators. Conversely, excess zinc added to the medium has shown to potentiate the stimulation of autophagy by tamoxifen, H2O2, ethanol and dopamine. The potential role of autophagy in zinc homeostasis has just begun to be investigated. Increasing evidence indicates that autophagy dysregulation causes significant changes in cellular zinc homeostasis. Autophagy may mediate the protective effect of zinc against lipid accumulation, apoptosis and inflammation by promoting degradation of lipid droplets, inflammasomes, p62/SQSTM1 and damaged mitochondria. Studies with humans and animal models are necessary to determine whether autophagy is influenced by zinc intake.
    BioMetals 07/2014; 27(6). DOI:10.1007/s10534-014-9773-0 · 2.50 Impact Factor
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