Mutation and expression analysis of the KRIT1 gene associated with cerebral cavernous malformations (CCM1)

Cavernous malformations are vascular anomalies that can cause severe neurological deficits, seizures and hemorrhagic stroke if these lesions are located in the brain. In patients with cavernomas, constitutional mutations of the KRIT1 gene have been identified. The pathogenetic mechanisms leading to cerebral cavernous malformations (CCM) development are poorly understood. CCM development might be induced in utero owing to the underlying KRIT1 defect, and is triggered by environmental factors. Another model suggests that CCM develop according to the two-hit model of tumorigenesis associated with biallelic inactivation of KRIT1. So far, CCM specimens themselves have not been subjected to mutation analysis. We identified two somatic mutations in the cavernoma of a sporadic case, suggesting that pathogenesis is associated with somatic KRIT1 alterations. To gain a better understanding of the role of KRIT1 during morphogenesis, the main goal of this study was to provide a detailed description of the spatio-temporal expression pattern of Krit1 and its interaction partner Rap1A during mouse embryogenesis. We did not observe enhanced expression of either gene in the heart or large vessels; however, their expression in the developing small vessels or capillaries could not be assessed by the methods applied. At early embryonic stages, Krit1 and, to a lesser extent, Rap1A are expressed in the developing nervous system. During later phases of fetal development, specific expression of both genes is observed in regions of ossification, the dermis, tendons and in the meninges. These findings provide evidence of differential Krit1 and Rap1A expression during mouse ontogenesis and suggest a more widespread functional significance of Krit1, not restricted to vascular endothelial cells.