Remarkable composition shift of cone subtypes combined with changes on phototransduction due to cone mosaicism induced by ARR3 variants

Heterozygous variants in ARR3, encoding cone arrestin, have been identified to cause high myopia with a unique X-linked female limited inheritance but the potential mechanism for the unusual anti-X-linked pattern is still unclear. Arr3 expression profiles showed that Arr3, with significant expression in retina since P14, was almost co-stained with Opsin red/green in cones including some partially co-stained with both Opsin red/green and Opsin blue. And then Arr3 knock-in mice and Arr3 knock-out rats were generated. A mosaic expression of Arr3 was present in rodents with Arr3 heterozygous deficiency according to retinal flat-mount staining. Retinal single-cell RNA sequencing revealed significant changes in proportion of three cone sub-clusters in Arr3+/- rats, namely significantly decreased M/S cones, and significantly increased S cones. Pde6h was the only one differentially expressed genes (DEGs) shred in M/S cones in the comparison group Arr3+/+ vs. Arr3+/- and Arr3-/0 vs. Arr3+/-, but not in Arr3+/+ vs. Arr3-/0. These results suggest that heterozygous Arr3 loss in cones causes mosaic changes of cone subtypes that might mimic defocus visual signals in phototransduction. Overall design: Retinal single-cell RNA sequencing (scRNA-seq) for subcluster of cones and gene expression changes in samples of the induced Arr3+/+, Arr3+/- and Arr3-/0 rats.