title: Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease.
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.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: French
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
authors.forename: Anita L
authors.initials: AL
authors.lastname: Destefano
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.forename: Corey R
authors.initials: CR
authors.lastname: Arnold
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Gage
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Skarie
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Millen
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: William
authors.initials: W
authors.lastname: Dietz
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kume
authors.forename: Marten
authors.initials: M
authors.lastname: Hofker
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Emery
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Childs
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Waskiewicz
authors.forename: Ordan J
authors.initials: OJ
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D002543:Cerebral Hemorrhage / Q000235:genetics; D059345:Cerebral Small Vessel Diseases / Q000235:genetics*; D018389:Codon, Nonsense; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics; D015810:Linkage Disequilibrium; D020125:Mutation, Missense; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D015027:Zebrafish; D000097577:Homeobox Protein PITX2
chemical_list: D018389:Codon, Nonsense; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D010982:Platelet-Derived Growth Factor; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C112743:FOXC1 protein, human