Functional characterization of a novel candidate gene for hereditary cerebral cavernous malformation

• Applicant: Professorin Dr. Ute Felbor
• Subject Area: Human Genetics
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246242579

Cerebral cavernous malformations (CCM) are vascular anomalies of the central nervous system. CCM generally become symptomatic during the second to fourth decade of life. Clinical symptoms include recurrent headaches, seizures, intracranial hemorrhage, and stroke. The prevalence of CCM is estimated to be 0.5%. CCM occur sporadically or in an autosomal dominantly inherited form. So far, disease-causing mutations were identified in three genes, CCM1 (1999), CCM2 (2003), and CCM3 (2005). The identification of human mutations in CCM1-3 and following functional analyses led to the recognition that these genes play essential roles in vasculo- and angiogenesis. The project aims at the functional characterization of a novel CCM disease gene identified by the applicants group using exome sequencing. Again, functions and structure of the gene product are currently unknown. Knockdown studies in zebrafish performed by one of the applicants co-workers already confirmed a vascular phenotype similar to ccm1 and ccm2 mutants thus suggesting an important role in vascular maturation and integrity. Therefore, a stable mutant zebrafish line is currently generated using the TALEN-technique. This line will be available and phenotypically characterized at the very beginning of the proposed project. In addition, the group intends to dissect the biological effects of the novel CCM gene product in endothelial cell cultures in vitro. In order to gain insight into the underlying molecular mechanisms, the group intends to identify and to characterize interaction partners using the yeast two-hybrid system and tyrosine kinase arrays which both have been used successfully in the past. Finally, the group wants to implement the TALEN-technique into endothelial cell cultures in order to develop a simple screen to test further candidate genes derived from exome analyses.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Participating Persons: Professor Dr. Andreas Fischer; Professor Dr. Stefan Schulte-Merker