Abstract
Familial idiopathic basal ganglia calcification (IBGC) is a genetic condition with a wide spectrum of neuropsychiatric symptoms, including parkinsonism and dementia. Here, we identified mutations in SLC20A2, encoding the type III sodium-dependent phosphate transporter 2 (PiT2), in IBGC-affected families of varied ancestry, and we observed significantly impaired phosphate transport activity for all assayed PiT2 mutants in Xenopus laevis oocytes. Our results implicate altered phosphate homeostasis in the etiology of IBGC.
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Acknowledgements
We would like to thank all the family members for their enthusiastic participation in the study. X.Z. would like to thank K. Hong, Q. Liu, Z. Wu, W. Xia, C. Zhang and L. Zou for clinical support. J.R.M.d.O. would like to thank R. Lemos and D. Oliveira for technical support. This study was mainly supported by the National Natural Science Foundation of China (30670736 and 30972655 to J.-Y.L. and 30730097 and 31021091 to X.Z.) and by the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT; IRT1006 to X.Z.). I.C.F. is supported by the Swiss National Science Foundation. M.L. is supported by the National Natural Science Foundation of China (30871386). J.R.M.d.O. is supported by the John Simon Guggenheim Memorial Foundation and by Conselho Nacional de Desenvolvimento Científico e Tecnológico M.-J.S. and B.Q. are supported by research contracts from the Institute of Health Carlos III and by FEDER funds. The study was approved by the ethics committees of HUST and Peking Union Medical College. Written informed consent was obtained from all participants or their legal guardians.
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J.-Y.L. conceived the study. J.-Y.L. and X.Z. designed the experiments, obtained financial support and wrote the paper. The group of J.-Y.L. discovered the first SLC20A2 mutation. X.Z. coordinated the subsequent international collaboration. C.W., Y.L., L.S. and J.R. carried out the linkage analysis and SLC20A2 mutation screening. L.S., L.W., C.W. and X.-Y.Z. were responsible for molecular cloning. M.P. and I.C.F. conducted 32Pi transport assays. Y.L. performed the bioinformatics analysis. T.W., J.R.M.d.O., M.-J.S., B.Q., M.B., H.X. and J.W. were responsible for clinical evaluation and sample collection. X.C., X.D., J.Y., J.L., L.Z., H.M., Y.G., X.M. and S.F. carried out mutation screening for other candidate genes. M.L. and Q.K.W. supported the genetic analyses.
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J.Y.L., X.Z., C.W., Y.L., L.S. and J.R. have filed a patent application related to the SLC20A2 sequences and variants. The patent application was filed with the Sate Intellectual Property Office (SIPO) of the People's Republic of China via the Patent Center of the Huazhong University of Science and Technology (HUST).
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Wang, C., Li, Y., Shi, L. et al. Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 44, 254–256 (2012). https://doi.org/10.1038/ng.1077
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DOI: https://doi.org/10.1038/ng.1077
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