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Abstract

Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.

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Acknowledgements

We wish to thank the participating family members for their valuable collaboration. We are thankful to B. Sobrino and J. Amigo for their help with exome sequencing, P. Cacheiro and I. König for help with data analysis and M. Delic and M. König for technical assistance. A. Keller holds a Marie Heim-Vögtlin fellowship from the Swiss National Science Foundation. A.W. is supported by the Fritz Thyssen Foundation, a Jake's Ride for Dystonia research grant through the Bachmann-Strauss Dystonia & Parkinson Foundation, a Habilitation Fellowship for Women Researchers (E26-2011) and by the Medical Genetics Priority Program from the University of Lübeck, Germany. M.J.S., M.G.-M., A.O.-U. and A.C. are supported by a research grant from the Xunta de Galicia, Consellería de Innovación (10PXIB9101280PR) and by European Regional Development (FEDER) funds. M.J.S. is the recipient of a research contract from the Institute of Health Carlos III. J.R.M.O., R.R.L. and J.E.G.d.C. are supported by grants from the John Simon Guggenheim Memorial Foundation, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundacão de Amparo à Ciênta e Tecnologia do Estado de Pernamnbuco (FACEPE) and Coordenacão de Aperfeicoamento de Pessoal de Nível Superior (CAPES). G.N., D.H. and D.C. are supported by funding of Centre National de Référence pour les Malades Alzheimer Jeunes (CNR-MAJ) by the French Ministry of Health and by the Rouen University Hospital. M.C.W. (Swiss National Science Foundation grant 310030_144075/1SNR) and the micro-CT unit (R'Equipe grant 3106030_139258/1) were supported by grants from the Swiss National Science Foundation. K.L. is supported by two research grants from the German Research Foundation (DFG) and by the Medical Genetics Priority Program of the University of Lübeck, Germany. V.D., I.P., M.J., I. Novaković and V.S.K. are supported by a research grant from the Serbian Ministry of Education and Science (project grant 175090). M.Z. is supported by FAPESP/389 CEPID (State of São Paulo Research Foundation and CNPq (Instituto Nacional de Ciência e Tecnologia de Células Tronco em Doenças Genéticas Humanas)). K.Z. is supported by a research grant from the University of Lübeck (E30/2011). A.A. is the recipient of an Advanced Grant of the European Research Council and is supported by grants from the European Union (PRIORITY and LUPAS), the Swiss National Science Foundation, the Foundation Alliance BioSecure, the Clinical Research Focus Program of the University of Zürich and the Novartis Research Foundation. D.H.G. was supported by the US National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS; R01 NS040752). C.B. is the recipient of an Advanced Grant of the European Research Council and is supported by grants from Uppsala University, the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Söderberg Foundation, the IngaBritt and Arne Lundberg Foundation, the Swedish Research Council, the Swedish Cancer Society and the Cardiovascular Program at Karolinska Institutet. C.K. is supported by a career development award from the Hermann and Lilly Schilling Foundation and by the Medical Genetics Priority Program of the University of Lübeck, Germany.

Author information

Author notes

    • Annika Keller
    • , Ana Westenberger
    • , Maria J Sobrido
    • , Christer Betsholtz
    • , Christine Klein
    •  & Joao R M Oliveira

    These authors jointly directed and contributed equally to this work.

Affiliations

  1. Institute for Neuropathology, University Hospital Zürich, Zürich, Switzerland.

    • Annika Keller
    • , Elisabeth J Rushing
    • , Michael Hugelshofer
    • , Regina Reimann
    • , Irina Abakumova
    •  & Adriano Aguzzi
  2. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

    • Annika Keller
    • , Maarja Andaloussi Mäe
    • , Elisabeth Raschperger
    •  & Christer Betsholtz
  3. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

    • Annika Keller
    • , Maarja Andaloussi Mäe
    • , Elisabeth Raschperger
    •  & Christer Betsholtz
  4. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.

    • Ana Westenberger
    • , Aloysius Domingo
    • , Katja Lohmann
    • , Katja Zschiedrich
    •  & Christine Klein
  5. Fundación Pública Galega de Medicina Xenómica, Servizo Galego de Saúde (SERGAS), Instituto de Investigaciones Sanitarias (IDIS), Clinical University Hospital, Santiago de Compostela, Spain.

    • Maria J Sobrido
    • , Maria García-Murias
    • , Andres Ordoñez-Ugalde
    •  & Angel Carracedo
  6. Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidad de Santiago de Compostela, Santiago de Compostela, Spain.

    • Maria J Sobrido
    • , Maria García-Murias
    • , Andres Ordoñez-Ugalde
    •  & Angel Carracedo
  7. Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Renee L Sears
    • , Elizabeth Spiteri
    •  & Daniel H Geschwind
  8. Keizo Asami Laboratory, Federal University of Pernambuco, Recife, Brazil.

    • Roberta R Lemos
    • , José E Gomes da Cunha
    •  & Joao R M Oliveira
  9. Institut National de la Santé et de la Recherche Médicla (INSERM) U1079, Institute for Research and Innovation in Biomedicine (IRIB), University Hospital and Faculty of Medicine, Rouen, France.

    • Gael Nicolas
    • , Didier Hannequin
    •  & Dominique Campion
  10. Department of Neurology, Rouen University Hospital, Rouen, France.

    • Gael Nicolas
    •  & Didier Hannequin
  11. Centre National de Référence pour les Malades Alzheimer Jeunes (CNR-MAJ), Rouen University Hospital, Lille University Hospital and Paris-Salpêtrière University Hospital, Rouen, France.

    • Gael Nicolas
    • , Didier Hannequin
    •  & Dominique Campion
  12. Center for Minimally Invasive and Endoscopic Neurosurgery, Clinic Hirslanden, Zürich, Switzerland.

    • Michael Hugelshofer
  13. Department of Diagnostic and Interventional Radiology, University Hospital Zürich, Zürich, Switzerland.

    • Moritz C Wurnig
    •  & Andreas Boss
  14. Center for Microscopy and Image Analysis, University of Zürich, Zürich, Switzerland.

    • Andres Kaech
  15. Institute of Neurology Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.

    • Valerija Dobričić
    • , Igor Petrović
    • , Milena Janković
    • , Ivana Novaković
    •  & Vladimir S Kostić
  16. Department of Medicine (Neurology), University of Toronto, Toronto, Ontario, Canada.

    • Janis M Miyasaki
  17. Human Genome Study Center, University of São Paulo, São Paulo, Brazil.

    • Mayana Zatz
  18. Klinikum Aschaffenburg, Aschaffenburg, Germany.

    • Jörg Klepper
  19. Department of Pathology and Laboratory Science, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Elizabeth Spiteri
  20. Department of Neurology, Clinical University Hospital, Santiago de Compostela, Spain.

    • Jose M Prieto
  21. Department of Neurology, Fundación Jiménez-Díaz, Madrid, Spain.

    • Inmaculada Navas
  22. Institute for Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.

    • Michael Preuss
    •  & Carmen Dering
  23. Translational Neuropharmacology, Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet and Neurology Clinic, Karolinska University Hospital, Huddinge, Stockholm, Sweden.

    • Martin Paucar
    •  & Per Svenningsson
  24. Department of Reproductive Genetics and Biotechnology, Reproductive Biotechnology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran.

    • Kioomars Saliminejad
  25. Genetic Research Center, University of Social Welfare and Rehabilitation Science, Tehran, Iran.

    • Hamid R K Khorshid
  26. INSERM Unité Mixte de Recherche Scientifique (UMRS) 975, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), Paris, France.

    • Isabelle Le Ber
  27. Université Pierre et Marie Curie, Université Paris 6, UMRS 975, Paris, France.

    • Isabelle Le Ber
  28. Centre National de la Recherche Scientifique (CNRS) UMR 7225, Paris, France.

    • Isabelle Le Ber
  29. Assistance Publique–Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Centre de Référence des Démences Rares, Paris, France.

    • Isabelle Le Ber
  30. Department of Neurology, Caen University Hospital, Caen, France.

    • Gilles Defer
  31. Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France.

    • Dominique Campion
  32. Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Giovanni Coppola
  33. Neuropsychiatry Department, Federal University of Pernambuco, Recife, Brazil.

    • Joao R M Oliveira

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Contributions

J.R.M.O., C.B., C.K. and V.S.K. initiated the project, which was subsequently developed and led jointly by A. Keller, A.W., M.J.S., C.B., C.K. and J.R.M.O. A. Keller, A.W., M.J.S., K.L., K.Z., I. Navas, C.B., C.K. and J.R.M.O. conceived the experiments. A. Keller, E.J.R., M.H., R.R., I.A., M.A.M., E.R., M.C.W., A.B. and A. Kaech performed the mouse experiments, which were financially supported by C.B. and A.A. A.W., M.J.S., M.G.-M., A.D., R.L.S., R.R.L., A.O.-U., G.N., J.E.G.d.C., K.L., V.D., A.C., I.P., J.M.M., M.Z., K.Z., J.K., E.S., J.M.P., I. Navas, M. Preuss, C.D., M.J., M. Paucar, P.S., K.S., H.R.K.K., I. Novaković, I.L.B., G.D., D.H., V.S.K., D.C., D.H.G., G.C., C.K. and J.R.M.O. recruited and examined patients, collected and analyzed human DNA and/or interpreted genetic data. C.B., A. Keller, A.W., M.J.S., C.K. and J.R.M.O. wrote the manuscript with critical input from A.D., K.L. and K.Z.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Annika Keller or Maria J Sobrido or Christer Betsholtz or Christine Klein.

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DOI

https://doi.org/10.1038/ng.2723

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