1. Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease
- Author
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French, Curtis R., Seshadri, Sudha, Destefano, Anita L., Fornage, Myriam, Arnold, Corey R., Gage, Philip J., Skarie, Jonathan M., Dobyns, William B., Millen, Kathleen J., Liu, Ting, Dietz, William, Kume, Tsutomu, Hofker, Marten, Emery, Derek J., Childs, Sarah J., Waskiewicz, Andrew J., and Lehmann, Ordan J.
- Subjects
Magnetic resonance imaging -- Usage ,Single nucleotide polymorphisms -- Research ,Cerebrovascular disease -- Risk factors -- Genetic aspects -- Research -- Diagnosis ,Health care industry - Abstract
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 FOXCI-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.sup.-/-] mutants displayed brain vascular phenotypes. Together, these results extend the genetic etiology of stroke and demonstrate an increasing developmental basis for human cerebrovascular disease., Introduction Stroke is a leading cause of morbidity and mortality, whose prevalence increases dramatically with age. Despite its substantial heritable basis, only a small number of causative genes have so [...]
- Published
- 2014
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