Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease

J Clin Invest. 2014 Nov;124(11):4877-81. doi: 10.1172/JCI75109. Epub 2014 Sep 24.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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

Substances

  • Codon, Nonsense
  • FOXC1 protein, human
  • Forkhead Transcription Factors
  • Homeodomain Proteins
  • Platelet-Derived Growth Factor
  • Transcription Factors
  • homeobox protein PITX2