Disruption of the blood-aqueous barrier and lens abnormalities in mice lacking lysyl oxidase-like 1 (LOXL1).

Purpose: Exfoliation syndrome (ES) is commonly associated with glaucoma, premature cataracts, and other ocular and systemic pathologies. LOXL1 gene variants are significantly associated with ES; however, the role of the protein in ES development remains unclear. The purpose of this study was to characterize the ocular phenotype in Loxl1(-/-) (null) mice.

Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss.

Mutations in whirlin cause either Usher syndrome type II (USH2), a deafness-blindness disorder, or nonsyndromic deafness. The molecular basis for the variable disease expression is unknown. We show here that only the whirlin long isoform, distinct from a short isoform by virtue of having two N-terminal PDZ domains, is expressed in the retina.

Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis.

RPGR-interacting protein-1 (RPGRIP1) is localized in the photoreceptor-connecting cilium, where it anchors the RPGR (retinitis pigmentosa GTPase regulator) protein, and its function is essential for photoreceptor maintenance. Genetic defect in RPGRIP1 is a known cause of Leber congenital amaurosis (LCA), a severe, early-onset form of retinal degeneration. We evaluated the efficacy of replacement gene therapy in a murine model of LCA carrying a targeted disruption of RPGRIP1.

Increased light exposure alleviates one form of photoreceptor degeneration marked by elevated calcium in the dark.

Background: In one group of gene mutations that cause photoreceptor degeneration in human patients, guanylyl cyclase is overactive in the dark. The ensuing excess opening of cGMP-gated cation channels causes intracellular calcium to rise to toxic levels. The Y99C mutation in guanylate cyclase-activating protein 1 (GCAP1) has been shown to act this way.

Increased choroidal neovascularization following laser induction in mice lacking lysyl oxidase-like 1.

Purpose: Age-related degradation of the elastic lamina in Bruch's membrane may have a permissive effect on the growth of choroidal neovascularization (CNV). This study investigated the influence of defective elastic fiber maintenance in the development of laser-induced CNV.

Methods: A mouse lacking lysyl oxidase-like (LOXL)-1, an enzyme essential for elastin polymerization, was studied.

AAV-mediated expression targeting of rod and cone photoreceptors with a human rhodopsin kinase promoter.

Purpose: Gene therapy for retinal degeneration requires well-defined promoters that drive expression in rod and cone photoreceptors. This study was undertaken to develop short, active derivatives of the human rhodopsin kinase (RK) gene promoter for targeting transgene expression in rods and cones. RK, also known as G protein-coupled receptor kinase 1 (GRK1), is a component of the light adaptation pathway expressed in rods and cones.

Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cells.

Usher syndrome type IIA (USH2A), characterized by progressive photoreceptor degeneration and congenital moderate hearing loss, is the most common subtype of Usher syndrome. In this article, we show that the USH2A protein, also known as usherin, is an exceptionally large ( approximately 600-kDa) matrix protein expressed specifically in retinal photoreceptors and developing cochlear hair cells. In mammalian photoreceptors, usherin is localized to a spatially restricted membrane microdomain at the apical inner segment recess that wraps around the connecting cilia, corresponding to the periciliary ridge complex described for amphibian photoreceptors.

Mpp4 is required for proper localization of plasma membrane calcium ATPases and maintenance of calcium homeostasis at the rod photoreceptor synaptic terminals.

Membrane palmitoylated protein 4 (Mpp4) is a member of the membrane-associated guanylate kinase family. We show that Mpp4 localizes specifically to the plasma membrane of photoreceptor synaptic terminals. Plasma membrane Ca(2+) ATPases (PMCAs), the Ca(2+) extrusion pumps, interact with an Mpp4-dependent presynaptic membrane protein complex that includes Veli3 and PSD95.

Rod and cone opsin mislocalization in an autopsy eye from a carrier of X-linked retinitis pigmentosa with a Gly436Asp mutation in the RPGR gene.

Purpose: We investigated whether opsin mislocalization occurs in photoreceptors in a female carrier of X-linked retinitis pigmentosa with a Gly436Asp mutation in the retinitis pigmentosa GTPase regulator gene (RPGR).

Design: Histologic findings in autopsy eyes from a carrier were compared with those from a normal female.

Methods: Frozen retinal sections from the periphery of one eye of the carrier and the normal were stained with antibodies against either human red or green opsins, blue cone opsin, or rhodopsin and labeled with fluorochrome conjugated secondary antibodies.

Rootletin interacts with C-Nap1 and may function as a physical linker between the pair of centrioles/basal bodies in cells.

Rootletin, a major structural component of the ciliary rootlet, is located at the basal bodies and centrosomes in ciliated and nonciliated cells, respectively. Here we investigated its potential role in the linkage of basal bodies/centrioles and the mechanism involved in such linkages. We show that rootletin interacts with C-Nap1, a protein restricted at the ends of centrioles and functioning in centrosome cohesion in interphase cells.

Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP.

Purpose: Retinitis pigmentosa GTPase regulator (RPGR) is a photoreceptor protein anchored in the connecting cilia by an RPGR-interacting protein (RPGRIP). Loss of RPGRIP causes Leber congenital amaurosis (LCA), a severe form of photoreceptor degeneration. The current study was an investigation of whether somatic gene replacement could rescue degenerating photoreceptors in a murine model of LCA due to a defect in RPGRIP.

The ciliary rootlet maintains long-term stability of sensory cilia.

The striated ciliary rootlet is a prominent cytoskeleton originating from basal bodies of ciliated cells. Although a familiar structure in cell biology, its function has remained unresolved. In this study, we carried out targeted disruption in mice of the gene for rootletin, a component of the rootlet.

A single, abbreviated RPGR-ORF15 variant reconstitutes RPGR function in vivo.

Purpose: The retinitis pigmentosa GTPase regulator (RPGR) is essential for the maintenance of photoreceptor viability. RPGR is expressed as constitutive and ORF15 variants because of alternative splicing. This study was designed to examine whether the retina-specific ORF15 variant alone could substantially substitute for RPGR function.

Histologic study of retinitis pigmentosa due to a mutation in the RP13 gene (PRPC8): comparison with rhodopsin Pro23His, Cys110Arg, and Glu181Lys.

Purpose: To evaluate the retina in autopsy eyes from patients over age 60 with autosomal dominant retinitis pigmentosa and a mutation in the RP13 gene (designated as PRPC8, Arg2310Gly), rhodopsin Pro23His, rhodopsin Cys110Arg, or rhodopsin Glu181Lys.

Design: Histologic study of the retina.

Methods: All eyes were prepared for electron microscopy within 12 hours after death.

Dominant, gain-of-function mutant produced by truncation of RPGR.

Purpose: The retinitis pigmentosa GTPase regulator (RPGR) is essential in the maintenance of photoreceptor viability. Mutations in the X-linked RPGR gene have generally been assumed to be recessive. This study was undertaken to investigate whether certain mutant RPGR alleles may act dominantly.

The retinitis pigmentosa GTPase regulator (RPGR)- interacting protein: subserving RPGR function and participating in disk morphogenesis.

Retinitis pigmentosa is a photoreceptor degenerative disease leading to blindness in adulthood. Leber congenital amaurosis (LCA) describes a more severe condition with visual deficit in early childhood. Defects in the retinitis pigmentosa GTPase regulator (RPGR) and an RPGR-interacting protein (RPGRIP) are known causes of retinitis pigmentosa and LCA, respectively.

Rootletin, a novel coiled-coil protein, is a structural component of the ciliary rootlet.

The ciliary rootlet, first recognized over a century ago, is a prominent structure originating from the basal body at the proximal end of a cilium. Despite being the largest cytoskeleton, its structural composition has remained unknown. Here, we report a novel 220-kD protein, designated rootletin, found in the rootlets of ciliated cells.

Histopathologic study of variation in severity of retinitis pigmentosa due to the dominant rhodopsin mutation Pro23His.

Purpose: To compare histopathologic findings in an autopsy eye of an 87-year-old woman with retinitis pigmentosa and the rhodopsin mutation Pro23His with findings in an autopsy eye of a 77-year-old female relative (first cousin) with retinitis pigmentosa and the same mutation.

Design: Histopathologic study.

Methods: One eye from each patient was prepared for light and electron microscopy within 5 hours after death.