Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 11, Pages 4877-4881Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI75109
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Funding
- National Eye Institute/NIH [EY014126, EY007003, R01 EY019484]
- Canadian Institutes of Health Research (CIHR) [MOP-133658, MOP-114902]
- Natural Sciences and Engineering Research Council
- Heart and Stroke Foundation of Canada postdoctoral fellowship
- American Society of Human Genetics Charles Epstein Trainee Award
- CIHR Training Grant in Genetics, Child Health and Development studentship
- Alberta Innovates [201201139] Funding Source: researchfish
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Patients with cerebral small-vessel disease (CSVD) exhibit perturbed end-artery function and have an increased risk for stroke and age-related cognitive decline. Here, we used targeted genome-wide association (GWA) analysis and defined a CSVD locus adjacent to the forkhead transcription factor FOXC1. Moreover, we determined that the linked SNPs influence FOXC1 transcript levels and demonstrated that patients as young as 1 year of age with altered FOXC1 function exhibit CSVD. MRI analysis of patients with missense and nonsense mutations as well as FOXC1-encompassing segmental duplication and deletion revealed white matter hyperintensities, dilated perivascular spaces, and lacunar infarction. In a zebrafish model, overexpression or morpholino-induced suppression of foxc1 induced cerebral hemorrhage. Inhibition of foxc1 perturbed platelet-derived growth factor (Pdgf) signaling, impairing neural crest migration and the recruitment of mural cells, which are essential for vascular stability. GWA analysis also linked the FOXC1-interacting transcription factor PITX2 to CSVD, and both patients with PITX2 mutations and murine Pitx2(-/-) mutants displayed brain vascular phenotypes. Together, these results extend the genetic etiology of stroke and demonstrate an increasing developmental basis for human cerebrovascular disease.
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