The first inborn error of manganese metabolism caused by mutations in SLC30A10, a newly identified manganese transporter

Abstract Background We have identified an autosomal recessively inherited disorder of manganese metabolism that causes manganese accumulation in liver and brain with characteristic MRI brain appearances of hyperintense basal ganglia on T1-weighted sequences. Most affected individuals present in childhood with difficulties walking and fine motor impairment due to dystonia. Movement disorder is accompanied by liver cirrhosis, and some patients have died at a young age following complications of cirrhosis. An adult-onset form of parkinsonism associated with hepatomegaly and hypermanganesaemia has also been described. Further characteristics of both phenotypes include polycythaemia and features of iron depletion. Methods Homozygosity mapping was performed using an Illumina CytoSNP-12. The candidate gene was sequenced on an ABI sequencer. Functional studies in the manganese-sensitive yeast strain Δpmr1 were performed using Gateway technology (Invitrogen). Findings Homozygosity mapping identified SLC30A10 as the affected gene, and homozygous sequence changes were found in all affected individuals. SLC30A10 had previously been presumed to belong to a class of zinc transporters. However, expression of human wildtype SLC30A10 in Δpmr1 rescued growth in high manganese conditions confirming its role in manganese transport. The presence of missense and nonsense mutations in SLC30A10 failed to restore manganese resistance. Interpretation Evidently, evolutionary changes in the aminoacid sequence have altered the substrate specificity of this transporter from zinc in yeast to manganese in mammalian cells. SLC30A10 is the first recognised human manganese transporter that, when defective, causes two distinct phenotypes—childhood onset dystonia and adult onset parkinsonism—that are associated with hepatic cirrhosis and polycythaemia. Present treatment strategies, including chelation therapy with disodium calcium edetate and iron supplementation, lead to significant improvement of clinical symptoms and blood manganese levels. Funding Action Medical Research.