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Vanlandewijck, MichaelKarolinska Institutet,Uppsala universitet,Vaskulärbiologi,Karolinska Inst, Novum, ICMC, SE-14157 Stockholm, Sweden.
(author)
Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification
- Article/chapterEnglish2015
Publisher, publication year, extent ...
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2015-11-23
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Public Library of Science (PLoS),2015
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electronicrdacarrier
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LIBRIS-ID:oai:DiVA.org:uu-272285
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-272285URI
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https://doi.org/10.1371/journal.pone.0143407DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:132572314URI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Primary Familial Brain Calcification (PFBC), a neurodegenerative disease characterized by progressive pericapillary calcifications, has recently been linked to heterozygous mutations in PDGFB and PDGFRB genes. Here, we functionally analyzed several of these mutations in vitro. All six analyzed PDGFB mutations led to complete loss of PDGF-B function either through abolished protein synthesis or through defective binding and/or stimulation of PDGF-R beta. The three analyzed PDGFRB mutations had more diverse consequences. Whereas PDGF-R beta autophosphorylation was almost totally abolished in the PDGFRB L658P mutation, the two sporadic PDGFRB mutations R987W and E1071V caused reductions in protein levels and specific changes in the intensity and kinetics of PLC. activation, respectively. Since at least some of the PDGFB mutations were predicted to act through haploinsufficiency, we explored the consequences of reduced Pdgfb or Pdgfrb transcript and protein levels in mice. Heterozygous Pdgfb or Pdgfrb knockouts, as well as double Pdgfb(+/-); Pdgfrb(+/-) mice did not develop brain calcification, nor did Pdgfrb(redeye/redeye) mice, which show a 90% reduction of PDGFR beta protein levels. In contrast, Pdgfb(ret/ret) mice, which have altered tissue distribution of PDGF-B protein due to loss of a proteoglycan binding motif, developed brain calcifications. We also determined pericyte coverage in calcification-prone and non-calcification-prone brain regions in Pdgfb(ret/ret) mice. Surprisingly and contrary to our hypothesis, we found that the calcification-prone brain regions in Pdgfb(ret/ret) mice model had a higher pericyte coverage and a more intact blood-brain barrier (BBB) compared to non-calcification-prone brain regions. While our findings provide clear evidence that loss-of-function mutations in PDGFB or PDGFRB cause PFBC, they also demonstrate species differences in the threshold levels of PDGF-B/PDGF-R beta signaling that protect against small-vessel calcification in the brain. They further implicate region-specific susceptibility factor(s) in PFBC pathogenesis that are distinct from pericyte and BBB deficiency.
Subject headings and genre
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Lebouvier, ThibaudUppsala universitet,Vaskulärbiologi
(author)
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Mae, Maarja AndaloussiUppsala universitet,Vaskulärbiologi(Swepub:uu)maaan970
(author)
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Nahar, KhayrunUppsala universitet,Vaskulärbiologi(Swepub:uu)khana914
(author)
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Hornemann, SimoneUniv Zurich, Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland.
(author)
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Kenkel, DavidUniv Zurich, Univ Zurich Hosp, Inst Diagnost & Intervent Radiol, CH-8091 Zurich, Switzerland.
(author)
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Cunha, Sara I.Uppsala universitet,Vaskulärbiologi,Ludwiginstitutet för cancerforskning,Science for Life Laboratory, SciLifeLab(Swepub:uu)sarcu762
(author)
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Lennartsson, JohanUppsala universitet,Ludwiginstitutet för cancerforskning,Science for Life Laboratory, SciLifeLab(Swepub:uu)johalenn
(author)
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Boss, AndreasUniv Zurich, Univ Zurich Hosp, Inst Diagnost & Intervent Radiol, CH-8091 Zurich, Switzerland.
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Heldin, Carl-HenrikUppsala universitet,Ludwiginstitutet för cancerforskning,Science for Life Laboratory, SciLifeLab(Swepub:uu)carlheld
(author)
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Keller, AnnikaUniv Zurich, Univ Zurich Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland.
(author)
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Betsholtz, ChristerKarolinska Institutet,Uppsala universitet,Vaskulärbiologi(Swepub:uu)chbet517
(author)
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Uppsala universitetVaskulärbiologi
(creator_code:org_t)
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In:PLOS ONE: Public Library of Science (PLoS)10:111932-6203
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