Heterozygous patients often exhibit a ‘second hit’ on the normal CCM allele in CCM endothelial cells (Akers et al., 2009; McDonald et al., 2011) and loss of function of P53 or Msh2, genes that maintain genome stability, ‘sensitize’ Krit1+/- or Pdcd10+/- mice for development of CCM. The gene discussed is MSH2; the disease is cerebral cavernous malformation.