Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease
- French, C.R., Seshadri, S., Destefano, A.L., Fornage, M., Arnold, C.R., Gage, P.J., Skarie, J.M., Dobyns, W.B., Millen, K.J., Liu, T., Dietz, W., Kume, T., Hofker, M., Emery, D.J., Childs, S.J., Waskiewicz, A.J., Lehmann, O.J.
- J. Clin. Invest. 124(11): 4877-81 (Journal)
- Registered Authors
- Childs, Sarah J., Lehmann, Ordan J., Skarie, Jonathan M., Waskiewicz, Andrew
- MeSH Terms
- Cerebral Hemorrhage/genetics
- Cerebral Small Vessel Diseases/genetics*
- Codon, Nonsense
- Forkhead Transcription Factors/genetics*
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Homeodomain Proteins/genetics*
- Linkage Disequilibrium
- Mutation, Missense
- Platelet-Derived Growth Factor/physiology
- Polymorphism, Single Nucleotide
- Quantitative Trait Loci
- Signal Transduction
- Transcription Factors/genetics*
- 25250569 Full text @ J. Clin. Invest.
French, C.R., Seshadri, S., Destefano, A.L., Fornage, M., Arnold, C.R., Gage, P.J., Skarie, J.M., Dobyns, W.B., Millen, K.J., Liu, T., Dietz, W., Kume, T., Hofker, M., Emery, D.J., Childs, S.J., Waskiewicz, A.J., Lehmann, O.J. (2014) Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease. J. Clin. Invest.. 124(11):4877-81.
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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes