Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.

Abstract

Cerebral cavernous malformations (CCMs) are vascular malformations mostly located within the central nervous system. Most deleterious variants are loss of function mutations in one of the three <i>CCM</i> genes. These genes code for proteins that form a ternary cytosolic complex with CCM2 as a hub. Very few <i>CCM2</i> missense variants have been shown to be deleterious by modifying the ternary CCM complex stability. To investigate the causality of novel missense <i>CCM2</i> variants detected in patients with CCM. The three CCM genes were screened in 984 patients referred for <i>CCM</i> molecular screening. Interaction between CCM1 and CCM2 proteins was tested using co-immunoprecipitation experiments for the <i>CCM2</i> missense variants located in the phosphotyrosine binding (PTB) domain. 11 distinct <i>CCM2</i> rare missense variants were found. Six variants predicted to be damaging were located in the PTB domain, four of them were novel. When co-transfected with CCM1 in HEK293T cells, a loss of interaction between CCM1 and CCM2 was observed for all six variants. We showed, using co-immunoprecipitation experiments, that CCM2 missense variants located in the PTB domain were actually damaging by preventing the normal interaction between CCM1 and CCM2. These data are important for diagnosis and genetic counselling, which are challenging in patients harbouring such variants.