title: XPR1 mutations are a rare cause of primary familial brain calcification.
abstract: Mutations in XPR1, a gene encoding an inorganic phosphate exporter, have recently been identified in patients with primary familial brain calcification (PFBC). Using Sanger sequencing, we screened XPR1 in 18 unrelated patients with PFBC and no SLC20A2, PDGFB, or PDGFRB mutation. XPR1 variants were tested in an in vitro physiological complementation assay and patient blood cells were assessed ex vivo for phosphate export. We identified a novel c.260T > C, p.(Leu87Pro) XPR1 variant in a 41-year-old man complaining of micrographia and dysarthria and demonstrating mild parkinsonism, cerebellar ataxia and executive dysfunction. Brain (123)I-Ioflupane scintigraphy showed marked dopaminergic neuron loss. Peripheral blood cells from the patient exhibited decreased phosphate export. XPR1 in which we introduced the mutation was not detectable at the cell surface and did not lead to phosphate export. These results confirm that loss of XPR1-mediated phosphate export function causes PFBC, occurring in less than 8 % of cases negative for the other genes, and may be responsible for parkinsonism.
authors.affiliation: Département de Neurologie, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France.|Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, 34293, Montpellier, France.|Université de Montpellier, Cedex 5, 34293, Montpellier, France.|Laboratory of Excellence EpiGenMed, Montpellier, France.|Laboratory of Excellence GR-Ex, Paris, France.
authors.forename: Uriel
authors.initials: U
authors.lastname: López-Sánchez
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, 34293, Montpellier, France.|Université de Montpellier, Cedex 5, 34293, Montpellier, France.|Laboratory of Excellence EpiGenMed, Montpellier, France.|Laboratory of Excellence GR-Ex, Paris, France.
authors.forename: Donatella
authors.initials: D
authors.lastname: Giovannini
authors.affiliation: Faculté de Médecine, Inserm U1079, University of Rouen, IRIB, Normandy University, 22 Boulevard Gambetta, 76183, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Richard
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, 34293, Montpellier, France.|Université de Montpellier, Cedex 5, 34293, Montpellier, France.|Laboratory of Excellence EpiGenMed, Montpellier, France.|Laboratory of Excellence GR-Ex, Paris, France.
authors.forename: Jawida
authors.initials: J
authors.lastname: Touhami
authors.affiliation: Département de Neurologie, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France.|Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: N'Guyen
authors.affiliation: Département de Neurologie, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France.|Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rudolf
authors.affiliation: Département de Neurologie, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Thibault-Stoll
authors.affiliation: Faculté de Médecine, Inserm U1079, University of Rouen, IRIB, Normandy University, 22 Boulevard Gambetta, 76183, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|Department of Genetics, Rouen University Hospital, Rouen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: Faculté de Médecine, Inserm U1079, University of Rouen, IRIB, Normandy University, 22 Boulevard Gambetta, 76183, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Genetics, Rouen University Hospital, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.affiliation: Faculté de Médecine, Inserm U1079, University of Rouen, IRIB, Normandy University, 22 Boulevard Gambetta, 76183, Rouen, France.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Research, Rouvray Psychiatric Hospital, Sotteville-Lès-Rouen, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, 34293, Montpellier, France. jean-luc.battini@igmm.cnrs.fr.|Université de Montpellier, Cedex 5, 34293, Montpellier, France. jean-luc.battini@igmm.cnrs.fr.|Laboratory of Excellence EpiGenMed, Montpellier, France. jean-luc.battini@igmm.cnrs.fr.|Laboratory of Excellence GR-Ex, Paris, France. jean-luc.battini@igmm.cnrs.fr.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Battini
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, 1919 Route de Mende, 34293, Montpellier, France. marc.sitbon@igmm.cnrs.fr.|Université de Montpellier, Cedex 5, 34293, Montpellier, France. marc.sitbon@igmm.cnrs.fr.|Laboratory of Excellence EpiGenMed, Montpellier, France. marc.sitbon@igmm.cnrs.fr.|Laboratory of Excellence GR-Ex, Paris, France. marc.sitbon@igmm.cnrs.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Sitbon
authors.affiliation: Faculté de Médecine, Inserm U1079, University of Rouen, IRIB, Normandy University, 22 Boulevard Gambetta, 76183, Rouen, France. gaelnicolas@hotmail.com.|Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen, France. gaelnicolas@hotmail.com.|CNR-MAJ, Rouen University Hospital, Rouen, France. gaelnicolas@hotmail.com.|Department of Genetics, Rouen University Hospital, Rouen, France. gaelnicolas@hotmail.com.
authors.forename: Gaël
authors.initials: G
authors.lastname: Nicolas
mesh_terms: D000328:Adult; D001927:Brain Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D002114:Calcinosis / Q000000981:diagnostic imaging / Q000235:genetics*; D005192:Family Health; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D009662:Nortropanes / Q000493:pharmacokinetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011877:Radionuclide Imaging; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D011991:Receptors, Virus / Q000235:genetics*; D014162:Transfection; D000089842:Xenotropic and Polytropic Retrovirus Receptor
chemical_list: D009662:Nortropanes; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D011991:Receptors, Virus; C000715267:XPR1 protein, human; D000089842:Xenotropic and Polytropic Retrovirus Receptor; C519528:ioflupane
keywords: Fahr disease; Idiopathic basal ganglia calcification; Phosphate export; Primary familial brain calcification; XPR1