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: 10.93). 02/2012; 90(3):467-77. DOI: 10.1016/j.ajhg.2012.01.017
Source: PubMed


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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    • "PET studies of in vivo dopamine release in human subjects with the SLC30A10 mutation, as well as in other human conditions of Mn intoxication, can assist in defining the relationship between chelation therapy-induced reversibility of movement abnormalities and Mn-induced inhibition of striatal dopamine release. On the other hand, iron supplementation had additive beneficial effects to the chelation treatment in these mutation carriers (DiToro Mammarella et al., 2014; Quadri et al., 2012; Stamelou et al., 2012; Tuschl et al., 2008), leading to the proposal of early treatment with both chelators and iron to prevent symptom progression (Lechpammer et al., 2014; Tuschl et al., 2008). However, the augmented signal intensity in the basal ganglia nuclei of SLC30A10 mutation carriers remained the same after these treatments (DiToro Mammarella et al., 2014; Stamelou et al., 2012; Tuschl et al., 2008), implying that Mn has long-lasting negative effects on the central nervous system that are resistant to the current therapeutic agents for Mninduced parkinsonism. "
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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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    • "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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