Abstract
Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is a progressive inherited retinal disorder characterized by photoreceptor cell death and genetic heterogeneity. Mutations in many genes have been implicated in the pathophysiology of RCD, but several others remain to be identified. Herein, we applied whole-exome sequencing to a consanguineous family with one subject affected with RCD and identified a homozygous nonsense mutation, c.226C>T (p.Arg76(∗)), in KIZ, which encodes centrosomal protein kizuna. Subsequent Sanger sequencing of 340 unrelated individuals with sporadic and autosomal-recessive RCD identified two other subjects carrying pathogenic variants in KIZ: one with the same homozygous nonsense mutation (c.226C>T [p.Arg76(∗)]) and another with compound-heterozygous mutations c.119_122delAACT (p.Lys40Ilefs(∗)14) and c.52G>T (p.Glu18(∗)). Transcriptomic analysis in mice detected mRNA levels of the mouse ortholog (Plk1s1) in rod photoreceptors, as well as its decreased expression when photoreceptors degenerated in rd1 mice. The presence of the human KIZ transcript was confirmed by quantitative RT-PCR in the retina, the retinal pigment epithelium, fibroblasts, and whole-blood cells (highest expression was in the retina). RNA in situ hybridization demonstrated the presence of Plk1s1 mRNA in the outer nuclear layer of the mouse retina. Immunohistology revealed KIZ localization at the basal body of the cilia in human fibroblasts, thus shedding light on another ciliary protein implicated in autosomal-recessive RCD.