Transgene-Induced Chromosomal Rearrangement With Aberrant Human Vascular Endothelial Growth Factor at the Optic Fissure Leads to Uveal Coloboma in Mice.

Purpose: The pathogenesis of uveal coloboma, a potentially blinding congenital ocular malformation, is incompletely understood. We characterize a novel mouse model of coloboma, Retinal and Iris Coloboma (RICO).

Methods: Transgenic mice were created by insertion of a human vascular endothelial growth factor-165 (hVEGF) gene driven by a neuron-specific enolase promoter. Mice were examined clinically and histologically, and the insertion site was characterized by fluorescence in situ hybridization and genomic sequencing. Gene expression changes were assessed with RNA sequencing, immunofluorescence, and in situ hybridization.

Results: RICO mice are viable in the homozygous state and exhibit fully penetrant autosomal semidominant coloboma. Coloboma is associated with persistence of periocular mesenchyme in the optic fissure, likely contingent on a specific, transgene insertion-induced genomic rearrangement on chromosome 13 that drives aberrant hVEGF expression. RICO eye cups exhibit altered expression of genes in the vicinity of the insertion site, where deletions of the human homologous locus were found in coloboma patients. RNA sequencing demonstrates changes in multiple coloboma-associated genes.

Conclusions: RICO represents a useful model for studying the pathogenesis of human coloboma.