Identfication And Characterization Of Coloboma Astrocyte Vascular Defect 1 (coasvad1), A Genetic Defect Leading To Congenital Coloboma And Vascular Abnormalities.

Abstract

Purpose:: The Coasvad1 mutation arose spontaneously on the B6.C3H-Large ^myd background. The defect is inherited in a dominant fashion. Affected mice demonstrate a phenotype that includes the presence of coloboma and tortuous retinal blood vessels as determined by indirect opthalmoscopy. The purpose of this study was to characterize the unique phenotype observed in Coasvad1 mice.

Methods:: The fundus was examined by indirect ophthalmoscopy, and its appearance was documented by fundus photography. Fluorescein angiography was employed to better visualize the retinal vasculature. Astrocytes were stained with anti-glial fibrillary acidic protein (anti-GFAP), and the morphology of the retina was assessed by histological examination.

Results:: The Coasvad1 mutation does not segregate with the B6.C3H-Large^myd allele. Coasvad1 mutant mice demonstrate the presence of coloboma and tortuous vasculature as early as 4 weeks of age, and these two phenotypes occur together with 100% concordance. Longitudinal observation of these mice by indirect ophthalmoscopy revealed a variable degree of phenotypic progression. To better visualize the vasculature and to assess vascular permeability, fluorescein angiography was performed on adult mice. Fluorescein angiography highlighted the abnormal retinal vascular pattern. Immunohistochemical studies with anti-GFAP indicated an abnormal astrocytic template with areas devoid of staining interspersed with areas that had puncate staining. Histological analysis confirmed the clinical observation of optic nerve colobomas. Vitreal vessels associated with fibroplasia was also observed. At 24 months, the nerve fiber layer was severely thinned, peripheral drop out of cells from the ganglion cell layer were noted. The ONL layer was ~80% of normal controls. The OPL appeared compressed with many ectopic photoreceptor cell bodies adjacent to the cell bodies of the secondary neurons.

Conclusions:: The Coasvad1 mutation causes a phenotype of early-onset congenital coloboma and vascular tortuosity. As the B6.C3H-Large^myd allele does not segregate with phenotype, it appears that Coasvad1 is a novel mutation. Because this phenotype is unusual, it is hoped that further investigation of this mutation will lead to a better understanding of the processes that guide retinal vascular development.

Keywords: retinal neovascularization • retinal degenerations: hereditary • genetics