Abstract WMP26: Missense Mutation in COL22A1 is Associated With Intracranial Aneurysms

Abstract

Background: Both environmental and genetic factors have been linked to the formation of intracranial aneurysms (IAs), but animal models to explore mechanisms underlying genetic risk factors of IAs in humans are lacking. Methods: To identify additional genes responsible for IA development, whole exome sequencing of the patients from seven selected families was performed. One of the identified variants found in all five affected members of one family was a missense mutation in the highly conserved triple-helix region of the collagen COL22A1 isoform, the function of which has not been previously known. This mutant variant was examined in zebrafish embryonic and adult models. Results: We demonstrated that COL22A1 is expressed in cranial tissues as well as in the cells between myotomes in the trunk and tail region of the zebrafish embryos. Early global overexpression of the human mutant but not human wild-type COL22A1 in the zebrafish embryos interfered with epiboly movements during gastrulation suggesting that the mutation has a deleterious dominant effect. We then used TALEN-engineered nucleases to generate a loss-of-function mutant in zebrafish col22a1 . The homozygous null mutants were viable as adults but exhibited increased abnormal blood accumulations in the eyes and cranial regions, suggestive of hemorrhages. We further notice abnormal lesions existed in the trunks of these adults caused by rupture of blood vessels. A subset of the mutant adults shows cardiac dilation and a phenotype consistent with dilated cardiomyopathy. We further demonstrated that the homozygous embryos show increased sensitivity to cardiovascular stress, which results in a greater percentage of embryos with intracranial hemorrhages. The mutant embryos also exhibited increased vascular permeability as demonstrated by nano-particle injection into the circulation of 4-day post fertilization embryos. Conclusions: Our results suggest that the function of COL22A1 is important in maintaining vascular integrity and that mutations in COL22A1 are a potential one genetic cause for intracranial aneurysms in humans.