The Retinal Ciliopathies

Abstract

While the functions of many of the proteins located in or associated with the photoreceptor cilia are poorly understood, disruption of the function of these proteins may result in a wide variety of phenotypes ranging from isolated retinal degeneration to more pleiotropic phenotypes. Systemic findings include neurosensory hearing loss, developmental delay, situs-inversus, infertility, disorders of limb and digit development, obesity, kidney disease, liver disease, and respiratory disease. The concept of "retinal ciliopathies" brings to attention the importance of further molecular analysis of this organelle as well as provides a potential common target for therapies for these disorders. The retinal ciliopathies include retinitis pigmentosa, macular degeneration, cone-dystrophy, cone-rod dystrophy, Leber congenital amaurosis, as well as retinal degenerations associated with Usher syndrome, primary ciliary dyskinesia, Senior-Loken syndrome, Joubert syndrome, Bardet-Biedl syndrome, Laurence-Moon syndrome, McKusick-Kaufman syndrome, and Biemond syndrome. Mutations for these disorders have been found in retinitis pigmentosa-1 (RP1), retinitis pigmentosa GTPase regulator (RPGR), retinitis pigmentosa GTPase regulator interacting protein (RPGR-IP), as well as the Usher, Bardet-Biedl, and nephronophthisis genes. Other systemic disorders associated with retinal degenerations that may also involve ciliary abnormalities include: Alstrom, Edwards-Sethi, Ellis-van Creveld, Jeune, Meckel-Gruber, Orofaciodigital Type 9, and Gurrieri syndromes. Understanding these conditions as ciliopathies may help the ophthalmologist to recognize associations between seemingly unrelated diseases and have a high degree of suspicion that a systemic finding may be present.

Somatostatin Signaling in Neuronal Cilia Is Criticalfor Object Recognition Memory

“…The role of cilia signaling in learning and memory has not been investigated, although ciliary defects that underlie BBS and Joubert syndrome are associated with mental retardation (Adams et al, 2007). However, since many developmental brain abnormalities are also apparent (Pan et al, 2005), a definitive link between cilia dysfunction and cognitive defects has not been established.…”

“…Mutations in ciliary genes lead to polycystic kidney disease, the most prevalent human genetic disease (Smith et al, 2006). Several such "ciliopathies" present diverse clinical phenotypes that include cognitive defects, such as Bardet-Biedl syndrome (BBS), Joubert syndrome, Meckel-Gruber syndrome (Adams et al, 2007), and hydrocephalus (Ibañez-Tallon et al, 2004;Town et al, 2008). Two different BBS-related proteins have been shown to be critical to localization of G-protein-coupled receptors, including somatostatin (SST) receptor subtype 3 (SST 3 ), to neuronal cilia (Berbari et al, 2008a).…”

Bardet–Biedl syndrome

“…4 Electroretinography is the investigation of choice and may show early changes within the first two years of life, although significant changes are rarely visible before the age of five. 12 Symptoms usually develop in the first decade of life and most patients are legally blind by the second or third decade, 13 although moderate forms of the disease do exist. Other eye abnormalities such as cataracts and refractive errors are also prevalent in BBS.…”

Accumulation of the Raf-1 Kinase Inhibitory Protein (Rkip) Is Associated with Cep290-mediated Photoreceptor Degeneration in Ciliopathies

“…These disorders are characterized by multiple clinical features including mental retardation, renal malfunction, and polydactyly. Photoreceptor degeneration, leading to retinitis pigmentosa (RP) and childhood onset Leber congenital amaurosis, is commonly observed in ciliopathies (13). However, the mechanism by which ciliary dysfunction results in photoreceptor degeneration is not clear.…”