Vascular malformations in the brain known as cerebral cavernous malformations (CCMs) are a cause of seizures and hemorrhagic stroke. Familial cases of CCM are caused by mutations in one of three genes – KRIT1, CCM2 or PDCD10 – and it has been hypothesised that the proteins they encode form a complex. However, Chan et al. now report that the molecular pathways perturbed by mutations in the different genes are distinct, despite causing similar clinical pathology. The authors used inducible, tissue-specific mouse models of CCM to show that loss of Pdcd10 has different effects on vascular development and endothelial signalling pathways than loss of Krit1 or Ccm2. Despite these differences, they found that loss of heterozygosity is the common genetic mechanism causing CCMs with both molecular phenotypes. These findings indicate that CCMs with similar pathology can be caused by multiple mechanisms, and that treatment strategies should take into account the causative mutation.
Chan A. C., Drakos S. G., Ruiz O. E., Smith A. C. H, Gibson C. C., Ling J., Passi S. F., Stratman A. N., Sacharidou A., Revelo M. P., et al. (2011). Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice. J. Clin. Invest. [Epub ahead of print]
https://doi.org/10.1172/JCI44393.
