title: Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice.
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.
authors.affiliation: Institute for Neuropathology, University Hospital Zürich, Zürich, Switzerland. annika.keller@usz.ch
authors.forename: Annika
authors.initials: A
authors.lastname: Keller
authors.forename: Ana
authors.initials: A
authors.lastname: Westenberger
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Sobrido
authors.forename: Maria
authors.initials: M
authors.lastname: García-Murias
authors.forename: Aloysius
authors.initials: A
authors.lastname: Domingo
authors.forename: Renee L
authors.initials: RL
authors.lastname: Sears
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Lemos
authors.forename: Andres
authors.initials: A
authors.lastname: Ordoñez-Ugalde
authors.forename: Gael
authors.initials: G
authors.lastname: Nicolas
authors.forename: José E Gomes
authors.initials: JE
authors.lastname: da Cunha
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Rushing
authors.forename: Michael
authors.initials: M
authors.lastname: Hugelshofer
authors.forename: Moritz C
authors.initials: MC
authors.lastname: Wurnig
authors.forename: Andres
authors.initials: A
authors.lastname: Kaech
authors.forename: Regina
authors.initials: R
authors.lastname: Reimann
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.forename: Valerija
authors.initials: V
authors.lastname: Dobričić
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Igor
authors.initials: I
authors.lastname: Petrović
authors.forename: Janis M
authors.initials: JM
authors.lastname: Miyasaki
authors.forename: Irina
authors.initials: I
authors.lastname: Abakumova
authors.forename: Maarja Andaloussi
authors.initials: MA
authors.lastname: Mäe
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Raschperger
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
authors.forename: Katja
authors.initials: K
authors.lastname: Zschiedrich
authors.forename: Jörg
authors.initials: J
authors.lastname: Klepper
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Spiteri
authors.forename: Jose M
authors.initials: JM
authors.lastname: Prieto
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Navas
authors.forename: Michael
authors.initials: M
authors.lastname: Preuss
authors.forename: Carmen
authors.initials: C
authors.lastname: Dering
authors.forename: Milena
authors.initials: M
authors.lastname: Janković
authors.forename: Martin
authors.initials: M
authors.lastname: Paucar
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.forename: Kioomars
authors.initials: K
authors.lastname: Saliminejad
authors.forename: Hamid R K
authors.initials: HR
authors.lastname: Khorshid
authors.forename: Ivana
authors.initials: I
authors.lastname: Novaković
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.forename: Andreas
authors.initials: A
authors.lastname: Boss
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.forename: Gilles
authors.initials: G
authors.lastname: Defer
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Kostić
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Giovanni
authors.identifier: 0000000321051061
authors.initials: G
authors.lastname: Coppola
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Joao R M
authors.initials: JR
authors.lastname: Oliveira
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001480:Basal Ganglia Diseases / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D023061:Gene Order; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010375:Pedigree; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics*; D014057:Tomography, X-Ray Computed
chemical_list: D020574:Proto-Oncogene Proteins c-sis
references.citation: J Neurol. 2011 Sep;258(9):1637-42
references.pmid: 21409505
references.citation: Eur J Neurol. 2013 Mar;20(3):e43-e44
references.pmid: 23406454
references.citation: NMR Biomed. 2010 Oct;23(8):913-21
references.pmid: 20878969
references.citation: Nature. 2010 Nov 25;468(7323):557-61
references.pmid: 20944627
references.citation: PLoS One. 2013;8(2):e57060
references.pmid: 23437308
references.citation: Neuroreport. 2006 May 15;17(7):717-21
references.pmid: 16641675
references.citation: Science. 1997 Jul 11;277(5323):242-5
references.pmid: 9211853
references.citation: Acta Neuropathol. 2005 Jun;109(6):643-53
references.pmid: 15937691
references.citation: Am J Hum Genet. 2010 Sep 10;87(3):354-64
references.pmid: 20727516
references.citation: Australas Radiol. 1998 Aug;42(3):232-3
references.pmid: 9727250
references.citation: Nat Genet. 2012 Feb 12;44(3):254-6
references.pmid: 22327515
references.citation: Geriatr Gerontol Int. 2013 Jul;13(3):706-10
references.pmid: 23279700
references.citation: Development. 2004 Apr;131(8):1847-57
references.pmid: 15084468
references.citation: J Neurosci Res. 2006 Jan;83(1):147-56
references.pmid: 16323208
references.citation: Genes Dev. 2007 Feb 1;21(3):316-31
references.pmid: 17289920
references.citation: Nucleic Acids Res. 1989 Aug 25;17(16):6591-601
references.pmid: 2780289
references.citation: Genes Dev. 2003 Aug 1;17(15):1835-40
references.pmid: 12897053
references.citation: Mol Biol Cell. 2000 Dec;11(12):4131-42
references.pmid: 11102513
references.citation: PLoS Comput Biol. 2010 Dec 02;6(12):e1001025
references.pmid: 21152010
references.citation: Genes Dev. 1994 Aug 15;8(16):1875-87
references.pmid: 7958863
references.citation: Clin Neurol Neurosurg. 1992;94(3):213-7
references.pmid: 1327610
references.citation: EMBO J. 2002 Aug 15;21(16):4307-16
references.pmid: 12169633
references.citation: PLoS Biol. 2003 Nov;1(2):E52
references.pmid: 14624252
references.citation: Development. 1999 Jun;126(14):3047-55
references.pmid: 10375497
references.citation: Hum Mutat. 2011 Aug;32(8):894-9
references.pmid: 21520341
references.citation: Physiol Rev. 1999 Oct;79(4):1283-316
references.pmid: 10508235
references.citation: Dev Biol. 2001 Feb 15;230(2):230-42
references.pmid: 11161575
references.citation: Neurogenetics. 2013 Feb;14(1):11-22
references.pmid: 23334463
references.citation: J Neurol. 1992 Jan;239(1):36-8
references.pmid: 1541967
references.citation: Acta Neuropathol. 1988;76(6):595-8
references.pmid: 2974228
references.citation: Genes Dev. 1994 Aug 15;8(16):1888-96
references.pmid: 7958864
references.citation: Nature. 2010 Nov 25;468(7323):562-6
references.pmid: 20944625
references.citation: Nat Neurosci. 2011 Jun;14(6):694-6
references.pmid: 21572432
references.citation: Neurology. 2013 Jan 8;80(2):181-7
references.pmid: 23255827
references.citation: Genes Dev. 2008 May 15;22(10):1276-312
references.pmid: 18483217