Development and Fate of Interphotoreceptor Matrix Components During Dysplastic Photoreceptor Differentiation: A Lectin Cytochemical Study of Rod-Cone Dysplasia 1

Mieziewska, Kristina; Veen, Theo van; Aguirre, Gustavo D.

doi:10.1006/exer.1993.1056

Cited by 13 publications

(9 citation statements)

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“…In contrast, the immunolabeling pattern of EZRIN, RLBP1 and MCT1 in cBest carrier retinae was comparable to that of the WT ( data not shown ). Confocal imaging of the mutant retinae immunolabeled by anti-EZRIN in combination with PNA lectin, known for its selective binding to the cone insoluble extracellular matrix microdomains (Johnson and Hageman, 1991; Mieziewska et al, 1993), confirmed MV retraction and revealed disordered and considerably disrupted cone-associated IPM ensheathment (Figs. 5G-J, and 6A-D).…”

Section: Bestrophinopathy: An Rpe-photoreceptor Interface Diseasementioning

confidence: 92%

Bestrophinopathy: An RPE-photoreceptor interface disease

Guziewicz

Sinha

Gómez

et al. 2017

Progress in Retinal and Eye Research

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Bestrophinopathies, one of the most common forms of inherited macular degenerations, are caused by mutations in the BEST1 gene expressed in the retinal pigment epithelium (RPE). Both human and canine BEST1-linked maculopathies are characterized by abnormal accumulation of autofluorescent material within RPE cells and bilateral macular or multifocal lesions; however, the specific mechanism leading to the formation of these lesions remains unclear. We now provide an overview of the current state of knowledge on the molecular pathology of bestrophinopathies, and explore factors promoting formation of RPE-neuroretinal separations, using the first spontaneous animal model of BEST1-associated retinopathies, canine Best (cBest). Here, we characterize the nature of the autofluorescent RPE cell inclusions and report matching spectral signatures of RPE-associated fluorophores between human and canine retinae, indicating an analogous composition of endogenous RPE deposits in Best Vitelliform Macular Dystrophy (BVMD) patients and its canine disease model. This study also exposes a range of biochemical and structural abnormalities at the RPE-photoreceptor interface related to the impaired cone-associated microvillar ensheathment and compromised insoluble interphotoreceptor matrix (IPM), the major pathological culprits responsible for weakening of the RPE-neuroretina interactions, and consequently, formation of vitelliform lesions. These salient alterations detected at the RPE apical domain in cBest as well as in BVMD- and ARB-hiPSC-RPE model systems provide novel insights into the pathological mechanism of BEST1-linked disorders that will allow for development of critical outcome measures guiding therapeutic strategies for bestrophinopathies.

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Section: Bestrophinopathy: An Rpe-photoreceptor Interface Diseasementioning

confidence: 92%

Bestrophinopathy: An RPE-photoreceptor interface disease

Guziewicz

Sinha

Gómez

et al. 2017

Progress in Retinal and Eye Research

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“…This complex, insoluble structure of poorly understood origin (29), forms an 'exoskeleton' that surrounds the RPE cone sheath, and cone IS and OS, and in photoreceptor degenerations it adjusts to the contours of the diseased cells (38). Preservation of this matrix domain will be critical for future studies with corrective gene therapy in order to provide the appropriate extracellular environment that would allow treated cones to regrow their OS.…”

Section: Developmental Abnormalities Of the Outer Retina And Oplmentioning

confidence: 99%

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

et al. 2016

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Ciliary defects can result in severe disorders called ciliopathies. Mutations in NPHP5 cause a ciliopathy characterized by severe childhood onset retinal blindness, Leber congenital amaurosis (LCA), and renal disease. Using the canine NPHP5-LCA model we compared human and canine retinal phenotypes, and examined the early stages of photoreceptor development and degeneration, the kinetics of photoreceptor loss, the progression of degeneration and the expression profiles of selected genes. NPHP5-mutant dogs recapitulate the human phenotype of very early loss of rods, and relative retention of the central retinal cone photoreceptors that lack function. In mutant dogs, rod and cone photoreceptors have a sensory cilium, but develop and function abnormally and then rapidly degenerate; L/M cones are more severely affected than S-cones. The lack of outer segments in mutant cones indicates a ciliary dysfunction. Genes expressed in mutant rod or both rod and cone photoreceptors show significant downregulation, while those expressed only in cones are unchanged. Many genes in celldeath and -survival pathways also are downregulated. The canine disease is a non-syndromic LCA-ciliopathy, with normal renal structures and no CNS abnormalities. Our results identify the critical time points in the pathogenesis of the photoreceptor disease, and bring us closer to defining a potential time window for testing novel therapies for translation to patients. †

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“…In the progressive rod-cone degeneration miniature poodle (Mieziewska et al, 1993b), the murine autosomal recessive nervous mutation (LaVail et al, 1993), and the rod-cone dysplasia 1 Irish setter (Mieziewska et al, 1993a), progressive photoreceptor degeneration occurs slowly, with rods being affected earlier and more severely than cones. As compartmentalization of the IPM is most obvious in the so-called cone matrix sheaths (Johnson et al, 1986), a correlation between the degenerative processes in these animals and the integrity of specific IPM domains has been suggested, although the nature of this relationship remains unclear (Mieziewska et al, 1993a, b;LaVail et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Genomic organization and chromosomal localization of the interphotoreceptor matrix proteoglycan-1 (IMPG1) gene: a candidate for 6q-linked retinopathies

Felbor

Gehrig²,

Sauer³

et al. 1998

Cytogenet Genome Res

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The interphotoreceptor matrix is a unique extracellular matrix occupying the space between the photoreceptors and the retinal pigment epithelium. Due to its putative function in the maintenance and integrity of the photoreceptor cells, it is conceivable that it is involved in retinal degeneration processes. More recently, a novel gene encoding a 150-kDa interphotoreceptor matrix proteoglycan, designated IMPG1, was cloned and shown to be expressed in both rod and cone photoreceptor cells. To assess this gene in human retinal dystrophies, we have now determined the genomic organization and chro- mosome location of IMPG1. It is composed of 17 exons ranging from 21 to 533 bp, including an alternatively spliced exon 2. Using somatic cell hybrid mapping and FISH analysis, we have assigned the IMPG1 locus to 6q13→q15. As this interval overlaps with the chromosomal loci of several human retinopathies, including autosomal dominant Stargardt-like macular dystrophy (STGD3), progressive bifocal chorioretinal atrophy (PBCRA), and North Carolina macular dystrophy (MCDR1), IMPG1 represents an attractive candidate for these 6q-linked disorders.

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Development and Fate of Interphotoreceptor Matrix Components During Dysplastic Photoreceptor Differentiation: A Lectin Cytochemical Study of Rod-Cone Dysplasia 1

Cited by 13 publications

References 0 publications

Bestrophinopathy: An RPE-photoreceptor interface disease

Bestrophinopathy: An RPE-photoreceptor interface disease

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

Genomic organization and chromosomal localization of the interphotoreceptor matrix proteoglycan-1 (IMPG1) gene: a candidate for 6q-linked retinopathies

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