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Mutations in SLC30A10 Cause Parkinsonism and Dystonia with Hypermanganesemia, Polycythemia, and Chronic Liver Disease

Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
The American Journal of Human Genetics (Impact Factor: 10.99). 02/2012; 90(3):467-77. DOI: 10.1016/j.ajhg.2012.01.017
Source: PubMed

ABSTRACT 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.

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    • "A homozygous mutation of the Mn transporter SLC30A10 causing severe hypermanganesemia, dystonia, parkinsonism, polycythemia, and chronic hepatic disease has recently been described [51]. SLC30A10 is highly expressed in the GP, subthalamic nucleus, putamen, deep cerebellar nuclei, and other diencephalic and cortical areas [51]. At the annual meeting of the American Academy of Neurology in 2013, Pretegiani and Rufa [52] presented two cases of SLC3A10 mutations with eye movement abnormalities similar to those found in our EP patients, including slow and hypometric horizontal saccades, but also a high error rate in the antisaccade task. "
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    ABSTRACT: Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson's disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro- and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system.
    PLoS ONE 08/2014; 9(8):e104784. DOI:10.1371/journal.pone.0104784 · 3.23 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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    • "Mutations in SLC30A10 cause extreme neurotoxic accumulation of Mn 2+ in liver and brain triggering dystonia and parkinsonism (Quadri et al., 2012). The subcellular localization of SLC30A10 matches with different compartments, such as the Golgi system, endosomes, and the plasma membrane (Quadri et al., 2012). The human SLC30A10 complements defective Mn 2+ uptake in yeast cells lacking the Ca 2+ /Mn 2+ ATPase PMR1 (Tuschl et al., 2012) and the endogenous SLC30A10 expression increases with Mn 2+ exposure in HepG2 hepatocellular carcinoma cells. "
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    ABSTRACT: Mutations in ATP13A2 lead to Kufor-Rakeb syndrome, a parkinsonism with dementia. ATP13A2 belongs to the P-type transport ATPases, a large family of primary active transporters that exert vital cellular functions. However, the cellular function and transported substrate of ATP13A2 remain unknown. To discuss the role of ATP13A2 in neurodegeneration, we first provide a short description of the architecture and transport mechanism of P-type transport ATPases. Then, we briefly highlight key P-type ATPases involved in neuronal disorders such as the copper transporters ATP7A (Menkes disease), ATP7B (Wilson disease), the Na(+)/K(+)-ATPases ATP1A2 (familial hemiplegic migraine) and ATP1A3 (rapid-onset dystonia parkinsonism). Finally, we review the recent literature of ATP13A2 and discuss ATP13A2's putative cellular function in the light of what is known concerning the functions of other, better-studied P-type ATPases. We critically review the available data concerning the role of ATP13A2 in heavy metal transport and propose a possible alternative hypothesis that ATP13A2 might be a flippase. As a flippase, ATP13A2 may transport an organic molecule, such as a lipid or a peptide, from one membrane leaflet to the other. A flippase might control local lipid dynamics during vesicle formation and membrane fusion events.
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