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.

Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

“…Furthermore, patients carrying SLC39A14 mutations showed excessive Mn accumulation in the whole blood and brain but a lack of Mn in the liver, possibly due to the bypassing of hepatic uptake by Mn and subsequent biliary excretion in the absence of SLC39A14 (37). SLC30A10, a Mn exporter, is expressed in the liver and may be the transporter that excretes Mn from hepatocytes into the bile canaliculi (26). We have shown for the first time to our knowledge that ZIP8 is localized to the apical canalicular membrane of the hepatocyte and promotes the reuptake of Mn from the bile into the hepatocyte, thus acting to defend against Mn deficiency.…”

“…Mn deficiency impairs bone formation, fertility, and the metabolism of glucose, lipids, and carbohydrates (20,23). Despite the essentiality of Mn, only divalent metal transporter 1 (DMT1) (24,25) and SLC30A10 (25,26) have been established as Mn transporters in vivo, and the physiological regulation of Mn metabolism is not well understood.…”

Nramp1 and Other Transporters Involved in Metal Withholding during Infection

“…Recent genetic studies identified mutations in the human gene that were associated with hypermanganesemia. Loading of this metal is observed in both tissues, resulting in cirrhosis of the liver and Parkinson-like motor impairments (94,95). Due to the roles of manganese (and zinc) in combating infection, one speculation is that this transporter may also participate in the host immune response.…”

Ferroportin deficiency impairs manganese metabolism in flatiron mice

“…For example, toxic effects of hypermanganesemia are seen in an inherited Mn overload syndrome associated with genetic defects in SLC30A10 (15,16). Recent studies have shown that SLC30A10 is a cell surfacelocalized Mn efflux transporter that reduces cellular Mn levels and protects against Mn toxicity (17,18).…”