Structural but Not Functional Alterations in Cones in the Absence of the Retinal Disease Protein Retinitis Pigmentosa 2 (RP2) in a Cone-Only Retina.

X-linked retinitis pigmentosa 2 (XLRP2) patients and mice exhibit severe cone photoreceptor degeneration. However, due to the paucity of cones in mammalian model systems, it is not clear how cones respond to the loss of RP2. Here we have used the mice, which develop a rodless and short wavelength (S) opsin-containing cone-only retina, to generate :: double knock out (-DKO) mice.

Prenylated retinal ciliopathy protein RPGR interacts with PDE6δ and regulates ciliary localization of Joubert syndrome-associated protein INPP5E.

Ciliary trafficking defects underlie the pathogenesis of severe human ciliopathies, including Joubert Syndrome (JBTS), Bardet-Biedl Syndrome, and some forms of retinitis pigmentosa (RP). Mutations in the ciliary protein RPGR (retinitis pigmentosa GTPase regulator) are common causes of RP-associated photoreceptor degeneration worldwide. While previous work has suggested that the localization of RPGR to cilia is critical to its functions, the mechanism by which RPGR and its associated cargo are trafficked to the cilia is unclear.

The carboxyl terminal mutational hotspot of the ciliary disease protein RPGRORF15 (retinitis pigmentosa GTPase regulator) is glutamylated in vivo.

Mutations inRPGR(ORF15)(retinitis pigmentosa GTPase regulator) are a major cause of inherited retinal degenerative diseases. RPGR(ORF15)(1152 residues) is a ciliary protein involved in regulating the composition and function of photoreceptor cilia. The mutational hotspot in RPGR(ORF15)is an unusual C-terminal domain encoded by exon ORF15, which is rich in polyglutamates and glycine residues (Glu-Gly domain) followed by a short stretch of basic amino acid residues (RPGR(C2)domain; residues 1072-1152).

Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR.

Mutations in RPGR (retinitis pigmentosa GTPase regulator) are the most common cause of X-linked RP, a severe blindness disorder. RPGR mutations result in clinically variable disease with early- to late-onset phenotypic presentation. Molecular mechanisms underlying such heterogeneity are unclear.

Loss of human disease protein retinitis pigmentosa GTPase regulator (RPGR) differentially affects rod or cone-enriched retina.

It is unclear how genes, such as RPGR (retinitis pigmentosa guanine triphosphatase regulator) that are expressed in both rods and cones, cause variable disease pathogenesis. Using transcriptomic analysis, we show that loss of RPGR in a rod-dominant mouse retina (Rpgr(ko)) results in predominant alterations in genes involved in actin cytoskeletal dynamics, prior to onset of degeneration. We validated these findings and found an increase in activated RhoA-GTP levels and polymerized F-actin in the Rpgr(ko) mouse retina.

Loss of retinitis pigmentosa 2 (RP2) protein affects cone photoreceptor sensory cilium elongation in mice.

Degeneration of photoreceptors (rods and cones) results in blindness. As we rely almost entirely on our daytime vision mediated by the cones, it is the loss of these photoreceptors that results in legal blindness and poor quality of life. Cone dysfunction is usually observed due to two mechanisms: noncell-autonomous due to the secondary effect of rod death if the causative gene is specifically expressed in rods and cell autonomous, if the mutation is in a cone-specific gene.

Ablation of retinal ciliopathy protein RPGR results in altered photoreceptor ciliary composition.

Cilia regulate several developmental and homeostatic pathways that are critical to survival. Sensory cilia of photoreceptors regulate phototransduction cascade for visual processing. Mutations in the ciliary protein RPGR (retinitis pigmentosa GTPase regulator) are a prominent cause of severe blindness disorders due to degeneration of mature photoreceptors.

Cilia in photoreceptors.

Retina is a neurosensory tissue lining the back of the eye and is responsible for light detection and relaying the signal to the visual cortex in the brain. Mammalian retina consists of six major types of neurons (including photoreceptors; rods and cones) and one type of glial cells arranged in distinct layers. Photoreceptors are the most abundant cell types accounting for approximately 60% of all cells in the retina.

Complex genetic mechanisms in glaucoma: an overview.

Glaucomas comprise a group of hereditary optic neuropathies characterized by progressive and irreversible visual field loss and damage to the optic nerve head. It is a complex disease with multiple molecular mechanisms underlying its pathogenesis. Genetic heterogeneity is the hallmark of all glaucomas and multiple chromosomal loci have been linked to the disease, but only a few genes have been characterized, viz.

A polymorphism in the CYP1B1 promoter is functionally associated with primary congenital glaucoma.

Primary congenital glaucoma (PCG) is a childhood autosomal-recessive disorder caused by developmental defects in the trabecular meshwork and anterior chamber angle. These defects cause raised intraocular pressure (IOP) that damages the optic nerve and if left untreated, results in irreversible blindness. Mutations in CYP1B1 gene at the GLC3A locus (2p21) are associated with PCG.

Variations in NTF4, VAV2, and VAV3 genes are not involved with primary open-angle and primary angle-closure glaucomas in an indian population.

Purpose: Recently, the neurotrophin-4 (NTF4), VAV2 and VAV3 genes have been implicated in primary open-angle glaucoma (POAG) in the European and Japanese populations, respectively. This study was conducted to determine their involvement in an Indian population with POAG and primary angle-closure glaucoma (PACG).

Methods: The entire NTF4 gene and the POAG-associated SNPs rs2156323 (VAV2) and rs2801219 (VAV3) and their flanking regions were screened by resequencing in a clinically well-characterized cohort of 537 subjects that included cases of POAG (n = 141), PACG (n = 111), and ethnically matched normal controls (n = 285).

The transcription factor gene FOXC1 exhibits a limited role in primary congenital glaucoma.

Purpose: Primary congenital glaucoma (PCG) is an autosomal recessive disorder that has been linked to CYP1B1 mutations. This study was conducted to explore the role of FOXC1, which is involved in anterior segment dysgenesis, in PCG.

Methods: An earlier screening for CYP1B1 in a clinically well-characterized PCG cohort (n = 301) revealed cases that were either homozygous (n = 73), compound heterozygous (n = 18), or heterozygous (n = 41) for the mutant allele, whereas the remaining (n = 169) did not harbor any mutation.

Exfoliation syndrome and exfoliation glaucoma-associated LOXL1 variations are not involved in pigment dispersion syndrome and pigmentary glaucoma.

Purpose: Single nucleotide polymorphisms (SNPs) in the LOXL1 gene have been implicated in exfoliation syndrome (XFS) and exfoliation glaucoma (XFG). We have shown that these SNPs are not associated with the primary glaucomas such as primary open-angle (POAG) glaucoma and primary angle-closure glaucoma (PACG). To further establish the specificity of LOXL1 SNPs for XFS and XFG, we determined whether these SNPs were involved in pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG).

The LOXL1 gene variations are not associated with primary open-angle and primary angle-closure glaucomas.

Purpose: Glaucoma is a complex disease involving multiple genetic factors. Recently, single nucleotide polymorphisms (SNPs) in the LOXL1 gene have been implicated in exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) but not in the primary glaucomas. This study was conducted to determine the possible involvement of these SNPs in cases of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG).