Abstract

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.

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Acknowledgements

We acknowledge and thank all of the participants and families for their valuable contributions to our study; our clinical staff and laboratory members, J. DeYoung and the University of California Los Angeles (UCLA) Neuroscience Genomics Core, J. Touhami and J. Laval for their assistance and constant support; and the National Heart, Lung, and Blood Institute (NHLBI) GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). We are also indebted to the Montpellier Rio Imaging (MRI) platform for flow cytometry experiments. This work was funded by the US National Institutes of Health/National Institute of Neurological Disorders and Stroke (R01NS040752 to D.H.G.), by Association Française contre les Myopathies (AFM) and Ligue Nationale contre le Cancer (Comité de l'Hérault; to J.-L.B.), and by Fondation pour la Recherche Médicale (FRM) and a FEDER European Union Languedoc-Roussillon grant (Transportome; to M.S.). We also acknowledge the support of the National Institute of Neurological Disorders and Stroke Informatics Center for Neurogenetics and Neurogenomics (PSNS062691). D.G. was supported by FRM, Institut National du Cancer (INCa) and Labex GR-Ex (ANR-11-LABX-0051) fellowships, and U.L.-S. was supported by a Labex EpiGenMed (ANR-10-LABX-12-01) fellowship; Labex is funded by the program 'Investissements d'Avenir' of the French National Research Agency. J.-L.B. and M.S. were supported by INSERM. M.-J.S. and B.Q. are supported by the Fondo de Investigación Sanitaria, grant PI12/00742; INNOPHARMA project MINECO-USC; and FEDER funds. M.-J.S. and B.Q. hold research contracts from the Institute of Health Carlos III–SERGAS. J.R.M.O. acknowledges funding from FACEPE (APQ 1831-4.01/12) and CNPq (457556/2013-7; 480255/2013-0; 307909/2012-3). B.L.F. is funded by US National Institutes of Health grants K08MH086297 (National Institute of Mental Health) and R01NS082094 (National Institute of Neurological Disorders and Stroke). G.N., A.-C.R., D.H. and D.C. are supported by INSERM, the University Hospital of Rouen and the French CNR-MAJ.

Author information

Author notes

    • Renee L Sears

    Present address: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Elizabeth Spiteri

    Present address: Kaiser Permanente Southern California Permanente Medical Group, Regional Reference Laboratories, Genetics Laboratory, Los Angeles, California, USA.

    • Andrea Legati
    •  & Donatella Giovannini

    These authors contributed equally to this work.

Affiliations

  1. Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Andrea Legati
    • , Renee L Sears
    • , Eliana Marisa Ramos
    • , Daniel H Geschwind
    •  & Giovanni Coppola
  2. Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, Montpellier, France.

    • Donatella Giovannini
    • , Uriel López-Sánchez
    • , Marc Sitbon
    •  & Jean-Luc Battini
  3. Université de Montpellier, Montpellier, France.

    • Donatella Giovannini
    • , Uriel López-Sánchez
    • , Marc Sitbon
    •  & Jean-Luc Battini
  4. Laboratory of Excellence GR-Ex, Paris, France.

    • Donatella Giovannini
    • , Uriel López-Sánchez
    • , Marc Sitbon
    •  & Jean-Luc Battini
  5. Laboratory of Excellence EpiGenMed, Montpellier, France.

    • Donatella Giovannini
    • , Uriel López-Sánchez
    • , Marc Sitbon
    •  & Jean-Luc Battini
  6. INSERM U1079, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Rouen, France.

    • Gaël Nicolas
    • , Anne-Claire Richard
    • , Dominique Campion
    •  & Didier Hannequin
  7. Centre National de Référence pour les Malades Alzheimer Jeunes (CNR-MAJ), Rouen University Hospital, Rouen, France.

    • Gaël Nicolas
    • , Anne-Claire Richard
    • , Dominique Campion
    •  & Didier Hannequin
  8. Department of Genetics, Rouen University Hospital, Rouen, France.

    • Gaël Nicolas
    •  & Didier Hannequin
  9. Fundación Pública Galega de Medicina Xenómica, Servizo Galego de Saúde (SERGAS), Instituto de Investigación Sanitaria (IDIS, Hospital Clínico Universitario), Santiago de Compostela, Spain.

    • Beatriz Quintáns
    • , María-Jesús Sobrido
    • , Ángel Carracedo
    •  & Cristina Castro-Fernández
  10. Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Universidad de Santiago de Compostela), Santiago de Compostela, Spain.

    • Beatriz Quintáns
    • , María-Jesús Sobrido
    • , Ángel Carracedo
    •  & Cristina Castro-Fernández
  11. Keizo Asami Laboratory, Federal University of Pernambuco, Recife, Brazil.

    • João R M Oliveira
  12. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Elizabeth Spiteri
    • , Brent L Fogel
    • , Joanna C Jen
    • , Daniel H Geschwind
    •  & Giovanni Coppola
  13. Neurology and Institute for Neurodegenerative Diseases, Bordeaux University Hospital and Bordeaux University, Bordeaux, France.

    • Stéphanie Cubizolle
    •  & François Tison
  14. Service de Génétique Médicale, Bordeaux Hospital University Center, Bordeaux, France.

    • Cyril Goizet
  15. Division of Medicine, Buriram Hospital, Buriram, Thailand.

    • Suppachok Kirdlarp
    • , Witoon Mitarnun
    •  & Suppachok Wetchaphanphesat
  16. Morton and Gloria Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.

    • Anthony E Lang
  17. Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Ontario, Canada.

    • Anthony E Lang
  18. Medical Genetics Group, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.

    • Zosia Miedzybrodzka
    •  & Sheila A Simpson
  19. Translational Neuropharmacology, Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.

    • Martin Paucar
    •  & Per Svenningsson
  20. Department of Neurology, Karolinska University Hospital Huddinge, Stockholm, Sweden.

    • Martin Paucar
    •  & Per Svenningsson
  21. Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.

    • Henry Paulson
  22. INSERM, Imagerie Cérébrale et Handicaps Neurologiques, UMR 825, Pole Neurosciences, Centre Hospitalier Universitaire (CHU) Purpan, Toulouse, France.

    • Jérémie Pariente
  23. CHU de Toulouse, Université de Toulouse, Toulouse, France.

    • Jérémie Pariente
  24. Barrow Neurological Institute, Phoenix, Arizona, USA.

    • Naomi S Salins
  25. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa 'G. Gaslini' Institute, Genoa, Italy.

    • Pasquale Striano
  26. Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.

    • Vivek K Unni
  27. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

    • Olivier Vanakker
  28. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Marja W Wessels
  29. Department of Pediatrics, Children's Hospital Colorado and University of Colorado Denver, Aurora, Colorado, USA.

    • Michele Yang
  30. Department of Neurology, George Washington University Medical School, Washington, DC, USA.

    • Francois Boller
  31. Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France.

    • Dominique Campion
  32. Department of Neurology, Rouen University Hospital, Rouen, France.

    • Didier Hannequin

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Contributions

M.S., D.H.G., J.-L.B. and G.C. designed the study. A.L., D.G., G.N. and U.L.-S. designed and performed experiments. A.L., D.G., G.N., U.L.-S., B.Q., J.R.M.O., L.S., E.M.R., E.S., M.-J.S., A.-C.R., D.C., M.S., D.H.G., J.-L.B. and G.C. analyzed data. A.L., D.G., M.S., J.-L.B. and G.C. wrote the manuscript. A.L., D.G., G.N., J.R.M.O., R.L.S., E.M.R., M.-J.S., B.L.F., A.E.L., Z.M., H.P., P. Striano, V.K.U., M.W.W., M.S., J.-L.B. and G.C. edited the manuscript. G.N., B.Q., J.R.M.O., E.S., M.-J.S., Á.C., C.C.-F., S.C., B.L.F., C.G., J.C.J., S.K., A.E.L., Z.M., W.M., M.P., H.P., J.P., N.S.S., S.A.S., P. Striano, P. Svenningsson, F.T., V.K.U., O.V., M.W.W., S.W., M.Y., F.B., D.H., D.H.G. and G.C. recruited and evaluated patients and collected blood samples.

Competing interests

J.-L.B. and M.S. are inventors on a provisional patent describing the use of ligands, including XRBD, for the analysis of human cells (PCT/EP2010/050139), and M.S. is a co-founder of METAFORA-biosystems, a start-up company that focuses on metabolite transporters under physiological and pathological conditions.

Corresponding authors

Correspondence to Jean-Luc Battini or Giovanni Coppola.

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DOI

https://doi.org/10.1038/ng.3289

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