Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice
Open accessAbstract
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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Loss-of-function mutations in endothelial PDGFB or pericyte PDGFRB genes can cause primary familial brain calcification, also known as idiopathic basal ganglia calcification or Fahr's disease, characterized by early onset of deep brain calcification, smooth muscle cells, pericyte loss, and neurological symptoms including motor and cognitive impairments.
“Loss-of-function mutations in endothelial PDGFB or pericyte PDGFRB genes can cause primary familial brain calcification also known as idiopathic basal ganglia calcification (IBGC) or Fahr's disease, which is characterized by early onset of deep brain calcification, SMCs, and pericyte loss and neurological symptoms including motor and cognitive impairments (309, 434).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [309]
Pericyte-deficient Pdgfb ret/ret mice develop deep brain calcification at a later age resembling idiopathic basal ganglia calcification.
“whereas pericyte-deficient Pdgfb ret/ret mice develop deep brain calcification at a later age resembling IBGC (309).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [309]
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References 36 · Cited by 324
- Authors
- Keller, A., Westenberger, A., Sobrido, M. J., García-Murias, M., Domingo, A., Sears, R. L., Lemos, R. R., Ordoñez-Ugalde, A., Nicolas, G., da Cunha, J. E. G., Rushing, E. J., Hugelshofer, M., Wurnig, M. C., Kaech, A., Reimann, R., Lohmann, K., Dobričić, V., Carracedo, A., Petrović, I., Miyasaki, J. M., Abakumova, I., Mäe, M. A., Raschperger, E., Zatz, M., Zschiedrich, K., Klepper, J., Spiteri, E., Prieto, J. M., Navas, I., Preuss, M., Dering, C., Janković, M., Paucar, M., Svenningsson, P., Saliminejad, K., Khorshid, H. R. K., Novaković, I., Aguzzi, A., Boss, A., Le Ber, I., Defer, G., Hannequin, D., Kostić, V. S., Campion, D., Geschwind, D. H., Coppola, G., Betsholtz, C., Klein, C., & Oliveira, J. R. M.
- Affiliations
- University Hospital Zurich (CH)
- University of Lübeck (DE)
- University of California, Los Angeles (US)
- Universidade Federal de Pernambuco (BR)
- Klinik Hirslanden (CH)
- University of Zurich (CH)
- University of Belgrade (RS)
- University of Toronto (CA)
- Uppsala University (SE)
- Universidade de São Paulo (BR)
- Klinikum Aschaffenburg (DE)
- Cedars-Sinai Medical Center (US)
- Complejo Hospitalario Universitario de Santiago (ES)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- Karolinska University Hospital (SE)
- Academic Center for Education, Culture and Research (IR)
- University of Social Welfare and Rehabilitation Sciences (IR)
- Centre Hospitalier Universitaire de Caen Normandie (FR)
- Inserm (FR)
- Corresponding author
- Keller, Annika
- ORCID
- Keller, Annika
- Westenberger, Ana
- Domingo, Aloysius
- Sears, Renee L
- Rushing, Elisabeth J
- Hugelshofer, Michael
- Wurnig, Moritz C
- Kaech, Andres
- Reimann, Regina
- Lohmann, Katja
- Petrović, Igor
- Miyasaki, Janis M
- Mäe, Maarja Andaloussi
- Zatz, Mayana
- Preuss, Michael
- Janković, Milena
- Paucar, Martin
- Svenningsson, Per
- Saliminejad, Kioomars
- Khorshid, Hamid R K
- Novaković, Ivana
- Aguzzi, Adriano
- Boss, Andreas
- Defer, Gilles
- Hannequin, Didier
- Campion, Dominique
- Geschwind, Daniel H
- Coppola, Giovanni
- Betsholtz, Christer
- Klein, Christine
- Venue
- Nature Genetics
- Published
- 2013-08-04
- Volume
- 45
- Issue
- 9
- Pages
- 1077-1082
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2076375535
- Cited by
- 324
- References
- 36
- Citations by year
- 2026: 8 · 2025: 29 · 2024: 24 · 2023: 22 · 2022: 21 · 2021: 24 · 2020: 27 · 2019: 32 · 2018: 25 · 2017: 31 · 2016: 27 · 2015: 26 · 2014: 22 · 2013: 5
- FWCI
- 14.97
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (134147)
- Topics
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Neurological and metabolic disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Keywords
- PDGF-B, platelet-derived growth factor B, PDGFRβ, Fahr disease, cerebral calcification, nonsense mutation, missense mutations, pericytes, blood-brain barrier, autosomal dominant inheritance
- MeSH terms
- Animals, Basal Ganglia Diseases, Brain, Calcinosis, Disease Models, Animal, Female, Humans, Magnetic Resonance Imaging, Male, Mutation, Pedigree, Tomography, X-Ray Computed, Mice, Knockout, Amino Acid Substitution, Proto-Oncogene Proteins c-sis, Gene Order, Mice
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