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

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Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man Karin Tuschl, Peter T. Clayton, Sidney M. Gospe, Shamshad Gulab, Shahnaz Ibrahim, Pratibha Singhi, Roosy Aulakh, Reinaldo T. Ribeiro, Orlando G. Barsottini, Maha S. Zaki, Maria Luz Del Rosario, Sarah Dyack, Victoria Price, Andrea Rideout, Kevin Gordon, Ron A. Wevers, W.K. “Kling” Chong, Philippa B. Mills The American Journal of Human Genetics Volume 90, Issue 3, Pages 457-466 (March 2012) DOI: 10.1016/j.ajhg.2012.01.018 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 SLC30A10 Mutations in Affected Families with a Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia (A) Mutations in SLC30A10 identified by DNA sequencing. (For families D and G no DNA was available for analysis of deceased siblings D-II-3 and G-II-1). (B) Genomic structure of the exons encoding SLC30A10 and positions of identified mutations. The large deletion spanning exon 1 and 2 in family A is indicated by a bracket. The American Journal of Human Genetics 2012 90, 457-466DOI: (10.1016/j.ajhg.2012.01.018) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Evolutionary Conservation Data for SLC30A10 Putative transmembrane domains marked I–VI in gray. Positions with single, fully conserved residues are marked with an asterisk (∗). Conservation between groups of strongly and weakly similar properties is indicated by a colon (;) and a period (.), respectively. Amino acid substitutions are marked in color: yellow, missense mutation (c.266T>C [p.Leu89Pro]); black arrows, deletion (c.298_402del, [p.Val98_Phe134del]); blue, deletion (c.314_322del [p.Ala105_Pro107del]); green, single base deletion causing frame shift and premature stop codon (c.585del [p.Thr196Profs∗17]); pink, deletion (c.765_767del [p.Val256 del]); orange, nonsense mutation (c.922C>T [p.Gln308∗]); red, missense mutation (c.1046T>C [p.Leu349Pro]). The American Journal of Human Genetics 2012 90, 457-466DOI: (10.1016/j.ajhg.2012.01.018) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Yeast Expression Studies Wild-type cells BY4743 and Δpmr1 cells were transformed with empty vector pYES-Dest52, SLC30A10, SLC30A10 (c.266T>C [p.Leu89Pro]), SLC30A10 (c.585del [p.Thr196Profs∗17]), ZRC1, and ZRC1 (c.131A>T [p.Asn44Ile]). 105, 5 × 104, 104, 5 × 103 and 103 cells (a–e) were spotted onto SC-Ura plates supplemented with or without 1.5 mM MnCl2 and incubated at 30°C for 6 days. Human SLC30A10 rescues growth of the manganese-sensitive Δpmr1 yeast strain on SC-Ura medium supplemented with high manganese concentration. Introducing the missense mutation (c.266T>C [p.Leu89Pro]) or nonsense mutation (c.585del [p.Thr196Profs∗17]) by site-directed mutagenesis abolishes the effect. The American Journal of Human Genetics 2012 90, 457-466DOI: (10.1016/j.ajhg.2012.01.018) Copyright © 2012 The American Society of Human Genetics Terms and Conditions