Genetics and Molecular Biology of Cerebral Cavernous Malformations and CCM Italia

Loss-of-function mutations of the KRIT1 gene (CCM1) have been associated with the pathogenesis of 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. However, the molecular and cellular functions of KRIT1 as well as CCM pathogenesis mechanisms remain incompletely understood. Indeed, experiments in animal models have raised the possibility that the loss-of-function of CCM genes may not be sufficient to cause lesion development, suggesting that the additional exposure of particularly sensitive microvascular districts to local stress events may contribute to the pathogenesis of CCM lesions. 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. Furthermore, we showed that KRIT1 loss-of-function causes a ROS-dependent upregulation of transcription factors involved in oxidative stress response, providing novel insights into the understanding of KRIT1 molecular and cellular functions, and supporting the hypothesis that CCM pathogenesis may result from impaired cell defences against local oxidative stress events in microvascular districts sensitized by CCM loss-of-function mutations. In addition, to facilitate further insights and breakthroughs into CCM pathogenesis mechanisms and their translational implementation, we organized the CCM_Italia multidisciplinary research network (CCM Italia, http://www.ccmitalia.unito.it/): an integrated research approach based on a team of clinicians and researchers with complementary expertise and interests related to diverse aspects of the CCM disease, including neurosurgeons, neurologists, neuroradiologists, pathological anatomists, geneticists, cellular and molecular biologists, and biotechnologists, which is aimed at information sharing and cooperation. Finally, we promoted a nonprofit patient-researcher organization (AIAC, Associazione Italiana Angiomi Cavernosi, http://www.ccmitalia.unito.it/aiac/), which is acting on a national scale as an informative and supportive platform to CCM patients, yet interacting with CCM-focused organizations active worldwide, including Angioma Alliance and Cavernoma Alliance UK.