Abstract
Purpose :
To characterize a robust genetic model of aberrant retinal angiogenesis in the mouse.
Methods :
While screening mouse strains and stocks at The Jackson Laboratory for models of human ocular disorders, we identified a new mouse model on the C57BL/KsJ background with abnormal retinal and subretinal vascularization. We characterized the pathological effects of the mutation by longitudinal examination of both mutant and control mice using indirect ophthalmoscopy, fluorescein angiography, image-guided optical coherence tomography (OCT), and histological studies to confirm aberrant retinal vascularization and by electroretinography (ERG) to test for effects on retinal function. Genetic analysis including linkage studies and candidate gene sequencing identified the causative gene and mutation.
Results :
The rnv4 mutation was discovered by indirect ophthalmoscopy in mice exhibiting pink-grey retinal lesions. The lesions were confirmed by fluorescein angiography and histology to be due to aberrant vascularization. Histology revealed blood vessels in the normally avascular subretinal space as early as postnatal day 14. ERG tests showed a progressive loss of rod ERG and delayed cone ERG responses compared to wild type control. Genetic analysis showed that the rnv4 is caused by an autosomal recessive mutation that mapped to mouse Chromosome 19 between D19Mit14 and D19Mit81, where the mouse very low density lipoprotein receptor (Vldlr) gene is located. Sequence analysis revealed that the rnv4 mutation is caused by a nucleotide substitution from A to G followed by a deletion of an adenine nucleotide in exon 12 of the Vldlr gene (AAAATAG change to AAGTAG). Due to the deletion, a frame shift leads to a stop codon at aa540.
Conclusions :
This spontaneous Vldlr mutation provides an additional model for aberrant retinal vascularization. The retinal angiogenesis phenotype in the rnv4 model is more consistent and robust than that observed in the Vldlrtm1Her targeted mutant mouse (stock #002529).
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.