Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man

Am J Hum Genet. 2012 Mar 9;90(3):457-66. doi: 10.1016/j.ajhg.2012.01.018. Epub 2012 Feb 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Brain / metabolism
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism
  • Child
  • Child, Preschool
  • Chromosome Mapping / methods
  • Codon, Nonsense*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Liver / metabolism
  • Male
  • Manganese / metabolism*
  • Manganese Poisoning / genetics*
  • Manganese Poisoning / metabolism
  • Metabolic Diseases / genetics*
  • Metabolic Diseases / metabolism*
  • Molecular Sequence Data
  • Mutation, Missense*
  • Saccharomyces cerevisiae / genetics
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Young Adult
  • Zinc Transporter 8

Substances

  • Cation Transport Proteins
  • Codon, Nonsense
  • SLC30A8 protein, human
  • Zinc Transporter 8
  • Manganese

Supplementary concepts

  • Hypermanganesemia with Dystonia Polycythemia and Cirrhosis