title: Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease.
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.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Quadri
authors.forename: Antonio
authors.initials: A
authors.lastname: Federico
authors.forename: Tianna
authors.initials: T
authors.lastname: Zhao
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.forename: Carla
authors.initials: C
authors.lastname: Battisti
authors.forename: Cathérine
authors.initials: C
authors.lastname: Delnooz
authors.forename: Lies-Anne
authors.initials: LA
authors.lastname: Severijnen
authors.forename: Lara
authors.initials: L
authors.lastname: Di Toro Mammarella
authors.forename: Andrea
authors.initials: A
authors.lastname: Mignarri
authors.forename: Lucia
authors.initials: L
authors.lastname: Monti
authors.forename: Antioco
authors.initials: A
authors.lastname: Sanna
authors.forename: Peng
authors.initials: P
authors.lastname: Lu
authors.forename: Francesca
authors.initials: F
authors.lastname: Punzo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cossu
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Rasi
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Bart P
authors.initials: BP
authors.lastname: van de Warrenburg
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping / Q000379:methods; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D056945:Hep G2 Cells; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008099:Liver / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000378:metabolism; D020149:Manganese Poisoning / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008659:Metabolic Diseases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D020734:Parkinsonian Disorders / Q000235:genetics*; D010641:Phenotype; D016415:Sequence Alignment / Q000379:methods; D014407:Tumor Cells, Cultured; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; D026901:Membrane Transport Proteins; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D008345:Manganese