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Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease
- Source :
- American Journal of Human Genetics, 90, 467-77, American Journal of Human Genetics, 90, 3, pp. 467-77, American Journal of Human Genetics, 90(3), 467-477. Cell Press
- Publication Year :
- 2012
-
Abstract
- Item does not contain fulltext 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.
- Subjects :
- Male
Cirrhosis
MANGANESE
ZINC
TRANSPORTER
EXPRESSION
FAMILY
IDENTIFICATION
CIRRHOSIS
GENES
ZNT-1
Chronic liver disease
Tumor Cells, Cultured
Genetics(clinical)
Frameshift Mutation
Cation Transport Proteins
Genetics (clinical)
Dystonia
Genetics
Parkinsonism
Manganese Poisoning
Homozygote
Brain
Chromosome Mapping
Hep G2 Cells
Middle Aged
Disease gene identification
Phenotype
Immunohistochemistry
Liver
Female
DCN MP - Plasticity and memory
Molecular Sequence Data
Genes, Recessive
Zinc Transporter 8
Biology
Article
Frameshift mutation
SDG 3 - Good Health and Well-being
Metabolic Diseases
Parkinsonian Disorders
medicine
Humans
Genetic Predisposition to Disease
Amino Acid Sequence
Aged
Manganese
Membrane Transport Proteins
medicine.disease
Cancer research
Steatosis
Sequence Alignment
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 90
- Database :
- OpenAIRE
- Journal :
- American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....7146f00dc8886d13e1e6f7ed73afc9a2