Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export.
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ABSTRACT:
SUBMITTER: Legati A
PROVIDER: S-EPMC4516721 | biostudies-literature | 2015 Jun
REPOSITORIES: biostudies-literature
Publications
Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export.
Legati Andrea A Giovannini Donatella D Nicolas Gaël G López-Sánchez Uriel U Quintáns Beatriz B Oliveira João R M JR Sears Renee L RL Ramos Eliana Marisa EM Spiteri Elizabeth E Sobrido María-Jesús MJ Carracedo Ángel Á Castro-Fernández Cristina C Cubizolle Stéphanie S Fogel Brent L BL Goizet Cyril C Jen Joanna C JC Kirdlarp Suppachok S Lang Anthony E AE Miedzybrodzka Zosia Z Mitarnun Witoon W Paucar Martin M Paulson Henry H Pariente Jérémie J Richard Anne-Claire AC Salins Naomi S NS Simpson Sheila A SA Striano Pasquale P Svenningsson Per P Tison François F Unni Vivek K VK Vanakker Olivier O Wessels Marja W MW Wetchaphanphesat Suppachok S Yang Michele M Boller Francois F Campion Dominique D Hannequin Didier D Sitbon Marc M Geschwind Daniel H DH Battini Jean-Luc JL Coppola Giovanni G
Nature genetics 20150504 6
Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC. ...[more]
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Project description:Solute carrier family 20 member 2 (SLC20A2) and xenotropic and polytropic retrovirus receptor 1 (XPR1) are transporters with phosphate uptake and efflux functions, respectively. Both are associated with primary familial brain calcification (PFBC), a genetic disease characterized by cerebral calcium-phosphate deposition and associated with neuropsychiatric symptoms. The association of the two transporters with the same disease suggests that they jointly regulate phosphate fluxes and cellular homeostasis, but direct evidence is missing. Here, we found that cross-talk between SLC20A2 and XPR1 regulates phosphate homeostasis, and we identified XPR1 as a key inositol polyphosphate (IP)-dependent regulator of this process. We found that overexpression of WT SLC20A2 increased phosphate uptake, as expected, but also unexpectedly increased phosphate efflux, whereas PFBC-associated SLC20A2 variants did not. Conversely, SLC20A2 depletion decreased phosphate uptake only slightly, most likely compensated for by the related SLC20A1 transporter, but strongly decreased XPR1-mediated phosphate efflux. The SLC20A2-XPR1 axis maintained constant intracellular phosphate and ATP levels, which both increased in XPR1 KO cells. Elevated ATP levels are a hallmark of altered inositol pyrophosphate (PP-IP) synthesis, and basal ATP levels were restored after phosphate efflux rescue with WT XPR1 but not with XPR1 harboring a mutated PP-IP-binding pocket. Accordingly, inositol hexakisphosphate kinase 1-2 (IP6K1-2) gene inactivation or IP6K inhibitor treatment abolished XPR1-mediated phosphate efflux regulation and homeostasis. Our findings unveil an SLC20A2-XPR1 interplay that depends on IPs such as PP-IPs and controls cellular phosphate homeostasis via the efflux route, and alteration of this interplay likely contributes to PFBC.
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