Cerebral cavernous malformations (CCMs) occur in brain and spinal vasculature. Described as appearing like mulberries in blood vessels, they are found in 0.5% of the population and may cause hemorrhagic stroke and epilepsy. A """"""""two-hit"""""""" mechanism has been proposed as a primary mechanism of CCM formation but has been difficult to prove. Consistent with a """"""""two-hit"""""""" mechanism, patients with the sporadic nonheritable form of CCM generally have a single CCM;whereas, patients with a heritable form usually have multiple CCMs. A """"""""two-hit"""""""" mechanism means that mutations knock-out both copies of a CCM gene in a cell that goes on to form the CCM lesion. Mutations in three genes, CCM1, CCM2 and CCM3 have been identified in heritable forms of CCM. If the """"""""two-hit"""""""" mechanism was true, individuals with a germline mutation in a CCM gene would also have a somatic mutation specific to the CCM lesion. Likewise, patients with a sporadic form of CCM would have two somatic mutations in a cell type that makes up the CCM lesion. Several investigations failed to find somatic mutations in CCM lesions. However, the methods used were likely not sensitive enough. In addition only one of three CCM genes was screened. We have identified somatic and heritable germline mutations in two CCM lesions that map to the endothelial cells lining the caverns. Improved methods investigating the endothelial cells of the lesion will be employed.
One aim with two projects is proposed to test the hypothesis that somatic mutations in the CCM1, CCM2 and CCM3 genes contribute to lesion genesis. The first project is to collect fresh frozen CCM lesions and characterize them into genetically distinguishable groups (sporadic non- heritable, heritable with known CCM1, 2 or 3 germline mutation and heritable without detectable germline mutation groups). The second project is to screen for CCM1, 2 and 3 somatic mutations in samples from sporadic cases and cases with known germline mutations. The proposed research is fundamental to understanding CCM pathogenesis.
Somatic mutations have been described as a major cryptic mechanism of common diseases because technologies that detect somatic mutations need to be developed. This proposal will develop new methods of somatic mutation detection and provide evidence of somatic mutation involvement in a common genetic disease, cerebral cavernous malformations, that predisposes to stroke and epilepsy.
| Gault, Judith; Awad, Issam A; Recksiek, Peter et al. (2009) Cerebral cavernous malformations: somatic mutations in vascular endothelial cells. Neurosurgery 65:138-44; discussion 144-5 |
