Cerebral Cavernous Malformations (CCM) and Intracranial Aneurysms (IA) are cerebrovascular disorders that can lead to a hemorrhagic stroke and other neurological problems. CCMs are characterized by abnormally enlarged capillary cavities while IAs are saccular outpouchings of intracranial arteries. CCM is found in approximately 0.4% to 0.9% of the population, while IA is more common (3-6%). / This dissertation aimed to add to the body of research for CCM and IA and was divided into two parts. Initial work focused on the characterization and identification of the genes involved in CCM; the second phase focused on the identification of a susceptibility gene for IA. / In the first phase, the CCM1, CCM2 and CCM3 genes were characterized in families and in sporadic cases of CCM. In both cohorts, a causative mutation was identified in 71% of the cases. Subsequent MLPA analysis of subjects with no CCM mutations revealed that large genomic deletions and duplications are a common cause of CCM. In addition, investigation of CCM1 point mutations revealed that these were not simple missense mutations but that they rather activated cryptic splice-donor sites and caused aberrant splicing. Furthermore, the genetic predisposition to CCM in sporadic cases with a single lesion was determined to be different from sporadic cases with multiple malformations. Investigation into the loss of heterozygosity demonstrated a plausible mechanism for CCM pathogenesis involving a second somatic hit at the site of the lesion, suggesting that CCM may be caused by a complete loss of CCM protein function. / In the second phase, a genome-wide scan of a large family and subsequent linkage analysis using a monogenic approach identified a susceptibility locus for IA (ANIB4). / As a result of this research, we have greatly contributed to the field of CCM, most specifically to its clinical diagnosis. A greater understanding of the genetics involved in CCM will facilitate and permit better management care for patients. Furthermore, the possibility of identification of a gene with a major effect for IA will give us more insight into which pathways are involved in IA formation.

No description available.