KRIT1, a disease gene responsible for cerebral cavernous malformations (CCM), is involved in cell defences against oxidative stress.

KRIT1 is a gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral haemorrhage. Comprehensive analysis of the KRIT1 gene in CCM patients has suggested that KRIT1 functions need to be severely impaired for pathogenesis. However, the molecular and cellular functions of KRIT1 as well as CCM pathogenesis mechanisms are still research challenges. Recently, we found that KRIT1 is involved in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage through an antioxidant pathway involving FoxO1 and SOD2. Moreover, we demonstrated that the role of KRIT1 in preventing the accumulation of intracellular ROS facilitates the downregulation of cyclin D1 expression required for cell transition from proliferative growth to quiescence (Goitre et al., 2010). Here, we report on updated studies that contribute to the unravelling of the KRIT1 role in the maintenance of homeostatic levels of ROS in cells, providing novel insights into the understanding of KRIT1 molecular and cellular functions, and raising the hypothesis that CCM pathogenesis may result from impaired endothelial cell defences against local oxidative stress events in sensitive cerebral microvascular districts carrying somatic or germline CCM mutations. P15 Molecular basis of cardiovascular diseases