Non-syndromic retinal ciliopathies: translating gene discovery into therapy

• Published in: Human molecular genetics 2012-10, Vol.21 (1), p.R111-R124
• Main Authors: ESTRADA-CUZCANO, Alejandro, ROEPMAN, Ronald, CREMERS, Frans P. M, DEN HOLLANDER, Anneke I, MANS, Dorus A
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biological Transport; Biotechnology; Cilia - genetics; Cilia - pathology; Disease Models, Animal; Dogs; Fundamental and applied biological sciences. Psychology; Gene therapy; Genetic Association Studies; Genetic Therapy; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Leber Congenital Amaurosis - genetics; Leber Congenital Amaurosis - pathology; Leber Congenital Amaurosis - therapy; Macular Degeneration - genetics; Macular Degeneration - pathology; Macular Degeneration - therapy; Mice; Molecular and cellular biology; Photoreceptor Cells - pathology; Retinal Degeneration - genetics; Retinal Degeneration - pathology; Retinal Degeneration - therapy; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - pathology; Retinitis Pigmentosa - therapy; Vision, Ocular - genetics; Vision, Ocular - physiology; Zebrafish
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/dds298

Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modifier 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 retinal degeneration affect the structure and/or function of the 'connecting cilium' in photoreceptors. This structure 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, connecting cilium and associated basal body, forms a highly specialized sensory cilium, fully dedicated to photoreception 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 congenital amaurosis (LCA), macular degeneration or retinitis pigmentosa (RP). The generation and characterization 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 augmentation 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.