Relatively Common Cause of Autosomal Recessive Early-Onset Retinal Degeneration in the Israeli and Palestinian Populations
Avigail Beryozkin, Lina Zelinger, Dikla Bandah-Rozenfeld, Anat Harel, Tim A. Strom, Saul Merin, Itay Chowers, Eyal Banin, Dror Sharon | Investigative Ophthalmology & Visual Science | March 2013 | Vol.54 | 2068-2075 |
Introduction Mutations in Crumbs homolog 1 (CRB1) are known to cause severe retinal dystrophies, ranging from Leber congenital amaurosis (LCA) to retinitis pigmentosa (RP). (1–7) LCA is the most severe nonsyndromic retinal dystrophy, characterized by blindness or severe visual impairment from birth, nonrecordable electroretinogram (ERG), nystagmus, hypermetropia, sluggish or absent pupillary responses, and oculodigital reflexes. (2,4–6,8) In contrast, RP is considered a milder and more heterogeneous disorder, with a later age of onset. It is characterized by night blindness followed by gradual loss of peripheral vision, progressive degeneration of photoreceptors, and eventually leads to visual impairment of variable severity that in rare cases can result in complete blindness. (9–12) Patients with RP have impaired ERG responses with a rod > cone pattern of injury, and over time suffer characteristic funduscopic findings, including bone spicule–like pigmentary (BSP) changes, attenuation of retinal vessels, and waxy pallor of the optic discs. (9–12)
Retinal dystrophies resulting from CRB1 mutations can be accompanied by additional specific features, including relative preservation of the para-arteriolar retinal pigment epithelium (PPRPE) and Coats-like vasculopathy. (1–5,8,13,14) RP with PPRPE is a form of RP characterized by preservation of the RPE that is adjacent to the retinal arterioles, while the rest of the RPE layer degenerates. Coats-like exudative vasculopathy is characterized by abnormal retinal vessels with increased permeability, leading to exudative retinal detachment that often is accompanied by massive subretinal lipid deposits. 3–5,7,13,15
CRB1 is a human homologue of the drosophila transmembrane crumbs protein, and is expressed in the brain and in the inner segments of mammalian photoreceptors. (2,3,7,16–19) The Crumbs protein is implicated in mechanisms that control cell-cell adhesion, intracellular communication and apicobasal cell polarity. For epithelial cells and photoreceptors, separation of their apical and basal compartments is critical for proper development and function of the cells and the tissue, including adhesion and signaling between and within cells.(2,7,13,16–19) Jacobson et al. suggested that CRB1 mutations underlie developmental defects in LCA, including thickening of the retina and lack of distinct layering in the fully developed adult retina.(13) Rashbass et al. postulated that CRB1 has a role in localizing phototransduction proteins to the apical membrane of the photoreceptors. 18 Thus, nonfunctional CRB1 may impede phototransduction, and lead to progressive dystrophy of the photoreceptors and the RPE, resulting in LCA or RP.
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