[HTML][HTML] Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease

CR French, S Seshadri, AL Destefano… - The Journal of …, 2014 - Am Soc Clin Investig
CR French, S Seshadri, AL Destefano, M Fornage, CR Arnold, PJ Gage, JM Skarie…
The Journal of clinical investigation, 2014Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation