Mutation and copy number variation of FOXC1 causes cerebral small vessel disease. C. R. French1, S. Seshadri2, A. L. Destefano3, M. Fornage4, D. J. Emery5, M. Hofker6, J. Fu6, A. J. Waskiewicz7, O. J. Lehmann1, 8 1) Ophthalmology, University of Alberta, Edmonton, AB, Canada; 2) Department of Neurology, Boston University, Boston, MA, U. S. A; 3) School of Public Health, Boston University, Boston, MA, U. S. A; 4) Institute of Molecular Medicine and School of Public Health, University of Texas Health Sciences Center, Houston, TX, U.S.A; 5) Department of Radiology, University of Alberta, Edmonton, AB, Canada; 6) Department of Medical Genetics, University Medical Center Groningen, Groningen, The Netherlands; 7) Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada; 8) Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.

   Cerebral small vessel disease (CSVD) represents a major risk factor for stroke and cognitive decline in the elderly. The ability to readily visualize its microangiopathic features by magnetic resonance imaging provides opportunities for using markers of CSVD to identify novel stroke associated pathways. Using targeted genome-wide association analysis we identified CSVD associated single nucleotide polymorphisms (SNPs) adjacent to the forkhead transcription factor FOXC1, and using eQTL analysis in two independent data sets, demonstrate that such SNPs are associated with FOXC1 expression levels. We further demonstrate, using magnetic resonance imaging, that patients with either FOXC1 mutation or copy number variation exhibit CSVD. These findings, present in patients as young as two years of age and observed with missense and nonsense mutations as well as FOXC1-encompassing segmental deletion and duplication, demonstrate FOXC1 dysfunction induces cerebral small vessel pathology. A causative role for FOXC1 in the development and maintenance of cerebral vasculature is supported by the cerebral hemorrhage generated by morpholino-induced suppression of FOXC1 orthologs in a zebrafish model system. Furthermore, in vivo imaging demonstrates profoundly impaired migration of neural crest cells and their subsequent association with nascent vasculature, a process required for the differentiation of perivascular mural cells. In addition, foxc1 inhibition reduces the expression of pdgfr, a gene critically required for vascular stability via its role in mural cell recruitment. Taken together, these data support a requirement for Foxc1 in stabilizing newly formed vasculature via recruitment of neural crest derived mural cells, and define a casual role for FOXC1 in cerebrovascular pathology.

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