Severe stroke, resulting from intracranial hemorrhage (ICH), is often associated with mutations in a small subset of genes, called CCM (cerebral cavernous malformation) genes. However, the variable clinical effects of CCM gene mutations are not understood. Aniket Gore and colleagues altered the expression of various CCM genes, or their effectors, in zebrafish embryos to study the genetic basis of susceptibility. Although reduced expression of individual CCM pathway proteins has little phenotypic effect, combinations of otherwise silent deficits disrupt endothelial junctions and result in a high incidence of ICH. Thus, small, individually silent defects in the CCM pathway strongly synergize to increase susceptibility to ICH.

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