Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man

• Autor(a) principal: Tuschl, Karin
• Data de Publicação: 2012
• Outros Autores: Clayton, Peter T., Gospe, Sidney M., Gulab, Shamshad, Ibrahim, Shahnaz, Singhi, Pratibha, Aulakh, Roosy, Ribeiro, Reinaldo T. [UNIFESP], Barsottini, Orlando G. [UNIFESP], Zaki, Maha S., Luz Del Rosario, Maria, Dyack, Sarah, Price, Victoria, Rideout, Andrea, Gordon, Kevin, Wevers, Ron A., Chong, W. K. "Kling", Mills, Philippa B.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: http://dx.doi.org/10.1016/j.ajhg.2012.01.018; http://repositorio.unifesp.br/handle/11600/34707

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 Delta pmr1. Expressing human wild-type SLC30A10 in the Delta pmr1 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.