Mutation of FOXC and PITX induces cerebral small-vessel disease

Curtis R. French, Sudha Seshadri, Anita L. Destefano, Myriam Fornage, Corey R. Arnold, Philip J. Gage, Jonathan M. Skarie, William B. Dobyns, Kathleen J. Millen, Ting Liu, William Dietz, Tsutomu Kume, Marten Hofker, Derek J. Emery, Sarah J. Childs, Andrew J. Waskiewicz, Ordan J. Lehmann

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


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 FOXC. Moreover, we determined that the linked SNPs influence FOXC transcript levels and demonstrated that patients as young as year of age with altered FOXC function exhibit CSVD. MRI analysis of patients with missense and nonsense mutations as well as FOXC-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 foxc induced cerebral hemorrhage. Inhibition of foxc 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 FOXC-interacting transcription factor PITX to CSVD, and both patients with PITX mutations and murine Pitx-/- mutants displayed brain vascular phenotypes. Together, these results extend the genetic etiology of stroke and demonstrate an increasing developmental basis for human cerebrovascular disease.

Original languageEnglish (US)
Pages (from-to)4877-4881
Number of pages5
JournalJournal of Clinical Investigation
Issue number11
StatePublished - Nov 3 2014
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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