Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice

• Published in: Nature genetics Vol. 45; no. 9; pp. 1077 - 1082
• Main Authors: Keller, Annika, Westenberger, Ana, Sobrido, Maria J, García-Murias, Maria, Domingo, Aloysius, Sears, Renee L, Lemos, Roberta R, Ordoñez-Ugalde, Andres, Nicolas, Gael, da Cunha, José E Gomes, Rushing, Elisabeth J, Hugelshofer, Michael, Wurnig, Moritz C, Kaech, Andres, Reimann, Regina, Lohmann, Katja, Dobričić, Valerija, Carracedo, Angel, Petrović, Igor, Miyasaki, Janis M, Abakumova, Irina, Mäe, Maarja Andaloussi, Raschperger, Elisabeth, Zatz, Mayana, Zschiedrich, Katja, Klepper, Jörg, Spiteri, Elizabeth, Prieto, Jose M, Navas, Inmaculada, Preuss, Michael, Dering, Carmen, Janković, Milena, Paucar, Martin, Svenningsson, Per, Saliminejad, Kioomars, Khorshid, Hamid R K, Novaković, Ivana, Aguzzi, Adriano, Boss, Andreas, Le Ber, Isabelle, Defer, Gilles, Hannequin, Didier, Kostić, Vladimir S, Campion, Dominique, Geschwind, Daniel H, Coppola, Giovanni, Betsholtz, Christer, Klein, Christine, Oliveira, Joao R M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2013; Nature Publishing Group
• Subjects: 631/378; Agriculture; Amino Acid Substitution; Animal Genetics and Genomics; Animals; Basal Ganglia Diseases - diagnosis; Basal Ganglia Diseases - genetics; Basal Ganglia Diseases - pathology; Biomedicine; Bone density; Brain - metabolism; Brain - pathology; Brain diseases; Brain research; Calcification; Calcinosis - genetics; Cancer Research; Colleges & universities; Councils; Disease Models, Animal; Female; Gene Function; Gene Order; Genetic aspects; Human Genetics; Humans; letter; Magnetic Resonance Imaging; Male; Mice; Mice, Knockout; Mutation; NMR; Nuclear magnetic resonance; Pedigree; Platelet-derived growth factor; Proteins; Proto-Oncogene Proteins c-sis - genetics; Risk factors; Tomography, X-Ray Computed; Brazil; United States
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2723

Christer Betsholtz, Christine Klein, Maria Sobrido and colleagues report the identification of mutations in the gene encoding PDGF-B that cause idiopathic basal ganglia calcification. They also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications. 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.