Abstracts

RATIONALE: Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. Using a genomic sequence-based positional cloning strategy, KRIT1 has recently been identified as the CCM1 gene, with a presumed founder effect in the Mexican-American population. KRIT1 encodes for a protein that interacts with the tumor suppressor protein Krev-1/rap1a. When mutated, KRIT1 may cause tumor-like proliferation of the vascular endothelial cells.
METHODS: With access to the extensive BNI neuropathology archive, retrospective screening of previously uncharacterized sporadic CCM patients can offer further evidence of the prevalence of KRIT1 mutations and aid in the isolation of additional CCM mutations. After validating a successful technique for harvesting viable DNA from paraffin-embedded tissue, the pathological specimens were sequenced to screen for KRIT1 mutations.
RESULTS: The preliminary conclusion of this study indicates that a number of patients, previously thought to be sporadic, may in fact carry a mutated KRIT1 gene. Ongoing investigations are also examining endothelial cells harvested by laser capture microdissection (LCM) for loss of heterozygosity.
CONCLUSIONS: Thus, the reported high incidence of KRIT1 mutations in patients with familial linkage may also apply to sporadic cases. Clinically, this finding may influence prospective screening of high-risk patients.
Support: The bulk of this project is supported by an American Heart Association-Bugher Foundation Award for the Investigation of Stroke Grant awarded to EWJ.