Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 ( Rp1 ) gene

Abstract

Retinitis pigmentosa (RP), a common group of human retinopathic diseases, is characterized by late-onset night blindness, loss of peripheral vision, and diminished or absent electroretinogram (ERG) responses. Mutations in the photoreceptor-specific gene RP1 account for 5-10% of cases of autosomal dominant RP. We generated a mouse model of the RP1 form of RP by targeted disruption of the mouse ortholog (Rp1) of human RP1. In Rp1 ؊͞؊ mice, the number of rod photoreceptors decreased progressively over a period of 1 year, whereas that of cone photoreceptors did not change for at least 10 months. Light and electron microscopic analysis revealed that outer segments of Rp1 ؊͞؊ rods and cones were morphologically abnormal and became progressively shorter in length. Before photoreceptor cell death, rhodopsin was mislocalized in inner segments and cell bodies of Rp1 ؊͞؊ rods. Rod ERG amplitudes of Rp1 ؊͞؊ mice were significantly smaller than those of Rp1 ؉͞؉ mice over a period of 12 months, whereas those of Rp1 ؉͞؊ mice were intermediate. The decreases in cone ERG amplitudes were slower and less severe than those in rods. These findings demonstrate that Rp1 is required for normal morphogenesis of photoreceptor outer segments and also may play a role in rhodopsin transport to the outer segments. The phenotype of Rp1 mutant mice resembles the human RP1 disease. Thus, these mice provide a useful model for studies of RP1 function, disease pathology, and therapeutic interventions. R etinitis pigmentosa (RP) is a common inherited retinopathy that affects Ϸ1 in 3,500 persons worldwide (1). Clinical findings in RP include progressive loss of night and peripheral vision that usually culminates in severe visual impairment or blindness. The disease is characterized by an abnormal or absent response on electroretinography (ERG) and is associated with retinal atrophy, deposition of pigment, and attenuation of retinal vessels. RP is heterogeneous clinically and genetically (2).We identified a gene, designated RP1, that is mutated in families with the RP1 form of autosomal dominant RP (3-8).The patients who are heterozygous for the RP1 mutations have very similar classic type 2 autosomal dominant RP phenotypes with relatively late onset of night blindness (usually by the third decade of life). However, within the same family, there is extensive variation in the age at which clinical disease is detected (7, 9). Moreover, in some families such as the UCLA-RP01, two members who are homozygous for an RP1 mutation have substantially more severe retinal degeneration than other family members who are heterozygous for the mutation (9). The human RP1 gene encodes a protein of 2,156 aa, the function of which is currently unknown. However, its N terminus shares significant homology with that of human doublecortin (DCX), a mutant form of which is involved in cerebral cortical abnormalities (10,11). This region of DCX is known to interact with microtubules (12, 13).To understand the function of the RP1 protein in the retina and the mechanism of reti...

The role of primary cilia in the development and disease of the retina

“…RP1 binds to singlet microtubules of the axoneme, 56 particularly at the point of disc membrane formation. In Rp1 mutant mice, disc membranes are abnormally organized 57 and discs do not stack correctly. RP1 is phosphorylated by MAK, and this is thought to regulate extension of the ciliary axoneme to control CC and OS length.…”

The DCX Superfamily 1: Common and Divergent Roles for Members of the Mouse DCX Superfamily

“…11,12 Mutations in this gene result in progressive blindness, not only in humans, but also in a mouse model. 13 Recently, an additional member of this protein family, doublecortin kinase 2, has been described, and found to posses MT binding activities. 14 The structure of the DCX domain is a ubiquitin-like fold, 15 different from that of classical MAPs.…”

Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model

“…Our observation of viral Bbs4 expression in the inner segment and proximal outer segment is entirely consistent with this idea. ScAAV5-mOP-BBS4 was able to reverse the prototypical rhodopsin mislocalization phenotype seen in several BBS mouse models (11,12,15), as well as other models in which ciliary proteins were deleted (31,32). It is not entirely clear whether rhodopsin mislocalization in this model is a direct result of Bbs4 deletion or rather a secondary insult caused by photoreceptor degeneration.…”