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Minzhong Yu, Mark Krebs, Lan Ying Shi, Jieping Wang, Wanda Hicks, Neal Peachey, Jürgen Naggert, Patsy Nishina; Retinal Tubulation and Detachment, Neovascularization and Retinal Pigment Epithelium Pathology in Slc4a5tvrm77 Mutant Mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1177.
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© ARVO (1962-2015); The Authors (2016-present)
To characterize a novel murine Slc4a5 allele associated with degenerative pathology of the retina and retinal pigment epithelium (RPE).
A mouse mutant exhibiting retinal abnormalities was discovered in an N-ethyl-N-nitrosourea mutagenesis ocular screen of C57BL/6J mice (Translational Vision Research Models program). The mutation was mapped to Chromosome 6 using DNA pooling and the candidate region narrowed by recombinational analysis. A whole exome capture library generated from DNA of an affected mouse was subjected to high throughput sequencing and analyzed using the Galaxy software program. The mutation was confirmed by RT-PCR of the candidate gene in two populations: the recombinant F2 intercross and the segregating colony on the C57BL/6J background. Pathological features and progression at one through six months of age were assessed by fundus imaging, optical coherence tomography and histology. Functional changes were assessed in wild type and mutant mice by electroretinography (ERG).
Genetic mapping and high-throughput sequencing identified a cryptic splice-site mutation in Slc4a5tvrm77, a gene encoding a putative sodium bicarbonate transporter. Slc4a5 mRNA levels were reduced ~10-fold in Slc4a5tvrm77 mutant RPE/choroid preparations. At one month of age, mutant mice exhibited branched white tubular lesions in the outer plexiform layer that appeared to connect with areas of abnormal pigment distribution within the RPE and subretinal space. Small areas of retinal detachment near the posterior pole were also observed. Detachment and tubular lesions were more extensive in older animals, often accompanied by retinal puckering. Retinal detachment and abnormal pigmented cell migration was confirmed by histology, which also provided evidence for neovascular structures in the subretinal space. In comparison to wild type, ERG a- and b-waves were slightly reduced at one and six months of age. The fast oscillation and light peak were reduced in amplitude at all ages, whereas the c-wave was not affected.
Slc4a5tvrm77 homozygous mice exhibit a complex degenerative pathology of the retina and RPE. A contribution of RPE defects to pathological progression is supported by retinal detachment and an abnormal RPE response to light at a disease stage where photoreceptor ERG responses are normal.
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