Mouse Slc9a8 mutants exhibit retinal defects due to retinal pigmented epithelium dysfunction

Purpose: As part of a large scale systematic screen to determine the effects of gene knockout mutations in mice, a retinal phenotype was found in mice lacking the Slc9a8 gene, encoding the sodium/hydrogen ion exchange protein NHE8. We aimed to characterise the mutant phenotype and the role of sodium/hydrogen ion exchange in retinal function. Methods: Detailed histology characterised the pathological consequences of Slc9a8 mutation, and retinal function was assessed by electroretinography (ERG). A conditional allele was used to identify the cells in which NHE8 function is critical for retinal function, and mutant cells analysed for the effect of the mutation on endosomes. Results: Histology of mutant retinas reveals a separation of photoreceptors from the retinal pigment epithelium (RPE) and infiltration by macrophages. There is a small reduction in photoreceptor length and a mislocalisation of visual pigments. ERG testing reveals a deficit in both rod and cone pathway function. The RPE shows abnormal morphology, and mutation of Slc9a8 in only RPE cells recapitulates the mutant phenotype. NHE8 localises to endosomes, and mutant cells have much smaller recycling endosomes. Conclusions: NHE8 is required in the RPE to maintain correct regulation of endosomal volume and/or pH which is essential for the cellular integrity and subsequent function of RPE.