Genetic mapping and characterization of nmf364a, a chemically-induced mutation leading to retinal degeneration

The objective of this study was to characterize and identify the gene mutated in nmf364a, a heritable chemically-induced inherited recessive mutation leading to retinal degeneration. Fundus imaging and histological analysis revealed progressive loss of photoreceptors (PRs) starting from one month of age, while ultrastructural and immunohistochemical analysis showed shortening of the PR outer segments, an accumulation of extracellular vesicles in the PR inner segments, and mis-localization of rhodopsin present at post-natal day 14 (P14). Genetic mapping localized the gene on mouse chromosome 5 and recombination analysis refined the critical region down to a 12,921,653 bp interval between D5Mit394 at 54,500,177 bp and rs13469874 at 67,421,830 bp. Sanger sequencing of candidate genes within the critical interval identified a point mutation in exon 34 of Wdr19 in nmf364a retinas. Wdr19 is a ciliary gene that encodes IFT144, a protein component of the IFT-A intra-cellular transport complex expressed in photoreceptor cells. In humans, mutations in Wdr19 have been most commonly associated with Senior-Loken syndrome, nephronophthisis, and short-rib thoracic dysplasia. Identification and characterization of this mutant variant of Wdr19 and its association with retinal degeneration without multisystemic involvement highlights the importance of genetic screening of Wdr19 in patients with arRP.