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: Marialuisa Quadri, Antonio Federico, Tianna Zhao, Guido J Breedveld, Carla Battisti, Cathérine Delnooz, Lies-Anne Severijnen, Lara Di Toro Mammarella, Andrea Mignarri, Lucia Monti, Antioco Sanna, Peng Lu, Francesca Punzo, Giovanni Cossu, Rob Willemsen, Fabrizio Rasi, Ben A Oostra, Bart P van de Warrenburg, Vincenzo Bonifati
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 90 Issue 3 Pg. 467-77 (Mar 09 2012) ISSN: 1537-6605 [Electronic] United States
• PMID: 22341971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• Aged
• Amino Acid Sequence
• Brain (metabolism)
• Cation Transport Proteins (genetics, metabolism)
• Chromosome Mapping (methods)
• Female
• Frameshift Mutation (genetics)
• Genes, Recessive
• Genetic Predisposition to Disease
• Hep G2 Cells
• Homozygote
• Humans
• Immunohistochemistry (methods)
• Liver (metabolism)
• Male
• Manganese (metabolism)
• Manganese Poisoning (genetics, metabolism)
• Membrane Transport Proteins (genetics, metabolism)
• Metabolic Diseases (genetics, metabolism)
• Middle Aged
• Molecular Sequence Data
• Parkinsonian Disorders (genetics)
• Phenotype
• Sequence Alignment (methods)
• Tumor Cells, Cultured
• Zinc Transporter 8