Non-syndromic retinal ciliopathies: translating gene discovery into therapy. HumMol Genet. 2012; 21: R111–124

Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modi-fier alleles implicated in inherited retinal degeneration in humans. To date, 158 genes have been found to be mutated in individuals with retinal dystrophies. Approximately one-third of the gene defects underlying ret-inal degeneration affect the structure and/or function of the ‘connecting cilium ’ in photoreceptors. This struc-ture corresponds to the transition zone of a prototypic cilium, a region with increasing relevance for ciliary homeostasis. The connecting cilium connects the inner and outer segments of the photoreceptor, mediating bi-directional transport of phototransducing proteins required for vision. In fact, the outer segment, connect-ing cilium and associated basal body, forms a highly specialized sensory cilium, fully dedicated to photore-ception and subsequent signal transduction to the brain. At least 21 genes that encode ciliary proteins are implicated in non-syndromic retinal dystrophies such as cone dystrophy, cone–rod dystrophy, Leber con-genital amaurosis (LCA), macular degeneration or retinitis pigmentosa (RP). The generation and characteriza-tion of vertebrate retinal ciliopathy animal models have revealed insights into the molecular disease mechanism which are indispensable for the development and evaluation of therapeutic strategies. Gene aug-mentation therapy has proven to be safe and successful in restoring long-term sight in mice, dogs and humans suffering from LCA or RP. Here, we present a comprehensive overview of the genes, mutations and modifier alleles involved in non-syndromic retinal ciliopathies, review the progress in dissecting the associated retinal disease mechanisms and evaluate gene augmentation approaches to antagonize retinal degeneration in these ciliopathies