ZFIN ID: ZDB-PUB-140925-4
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.
Date: 2014
Source: J. Clin. Invest.   124(11): 4877-81 (Journal)
Registered Authors: Childs, Sarah J., Lehmann, Ordan J., Skarie, Jonathan M., Waskiewicz, Andrew
Keywords: none
MeSH Terms:
  • Animals
  • 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*
  • Humans
  • Leukoencephalopathies/genetics
  • Linkage Disequilibrium
  • Mutation, Missense
  • Platelet-Derived Growth Factor/physiology
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Signal Transduction
  • Transcription Factors/genetics*
  • Zebrafish
PubMed: 25250569 Full text @ J. Clin. Invest.
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.