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Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease.
- Source :
-
Journal of Clinical Investigation . Nov2014, Vol. 124 Issue 11, p4877-4881. 5p. 3 Color Photographs. - Publication Year :
- 2014
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CEREBRAL small vessel diseases
*STROKE
*GENETIC mutation
*GENOMES
*CARDIOVASCULAR diseases
*BRAIN diseases
*ANIMAL experimentation
*CEREBRAL hemorrhage
*CELLULAR signal transduction
*COMPARATIVE studies
*DISEASE susceptibility
*FISHES
*GENES
*GENETIC polymorphisms
*GENETICS
*RESEARCH methodology
*MEDICAL cooperation
*PLATELET-derived growth factor
*PROTEINS
*RESEARCH
*RESEARCH funding
*TRANSCRIPTION factors
*EVALUATION research
*SEQUENCE analysis
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 124
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 99329847
- Full Text :
- https://doi.org/10.1172/JCI75109