The Manton Center for Orphan Disease Research
John D. Mably, PhD
Characterizing the cellular function of cerebral cavernous malformation associated genes
Cerebral Cavernous Malformations (CCMs) are vascular lesions that originate in the central nervous system. They appear as tangles of malformed blood vessels located in the brain and/or spinal cord. This collection of dilated, irregularly shaped small blood vessels (capillaries) often exhibits a characteristic honeycomb-like pattern. Although most are asymptomatic until the second or third decade of life they may also be detected in children where they can have devastating clinical consequences. Because of the dramatic dilation of the blood vessels within the lesion, the walls of the vessels are weak and also lack supporting tissue. For this reason, they are prone to bleeding and when observed under a microscope appear as large, bloodfilled caverns (for this reason, are also called cavernomas or cavernous angiomas). Unlike an aneurysm which is characterized by sudden rupture and acute clinical impact, the characteristic feature of a CCM is slow bleeding or oozing. Greater than 30% of patients with these lesions eventually develop symptoms which can range from seizures or hemorrhagic stroke to severe neurologic deficit. Mutations in three genes have been associated with this disease through the study of inherited forms. The Mably laboratory uses zebrafish to model human cardiovascular disease and I have identified and characterized zebrafish mutants with defects in two of these CCM genes (CCM1 and CCM2 respectively, in zebrafish). Additionally, through analysis of a third zebrafish mutant with an indistinguishable phenotype,Dr. Mably has identified the gene, a transmembrane molecule that is a novel component of the CCM pathway. The Mably Lab will use the zebrafish models to characterize the cellular functions of these proteins. Additionally,they will identify molecules downstream of the Heg protein that are involved in the formation of the CCM defects in the zebrafish models. This approach will help identify new targets for non-surgical therapies for CCM.