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.
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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.
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Keller, A., Westenberger, A., Sobrido, M. et al. Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet 45, 1077–1082 (2013). https://doi.org/10.1038/ng.2723
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DOI: https://doi.org/10.1038/ng.2723
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