title: Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man.
abstract: 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.
authors.affiliation: Clinical and Molecular Genetics Unit, University College London Institute of Child Health, UK. k.tuschl@ucl.ac.uk
authors.forename: Karin
authors.initials: K
authors.lastname: Tuschl
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Gospe
authors.forename: Shamshad
authors.initials: S
authors.lastname: Gulab
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Pratibha
authors.initials: P
authors.lastname: Singhi
authors.forename: Roosy
authors.initials: R
authors.lastname: Aulakh
authors.forename: Reinaldo T
authors.initials: RT
authors.lastname: Ribeiro
authors.forename: Orlando G
authors.initials: OG
authors.lastname: Barsottini
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Del Rosario
authors.forename: Sarah
authors.initials: S
authors.lastname: Dyack
authors.forename: Victoria
authors.initials: V
authors.lastname: Price
authors.forename: Andrea
authors.initials: A
authors.lastname: Rideout
authors.forename: Kevin
authors.initials: K
authors.lastname: Gordon
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: W K Kling
authors.initials: WK
authors.lastname: Chong
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping / Q000379:methods; D018389:Codon, Nonsense; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008345:Manganese / Q000378:metabolism*; D020149:Manganese Poisoning / Q000235:genetics* / Q000378:metabolism; D008659:Metabolic Diseases / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012441:Saccharomyces cerevisiae / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D055815:Young Adult; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; D018389:Codon, Nonsense; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D008345:Manganese