Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions.
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SUBMITTER: Brandl C
PROVIDER: S-EPMC5541303 | biostudies-other | 2017 Jun
REPOSITORIES: biostudies-other
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Project description:Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases caused by progressive degeneration of the photoreceptor cells. Using autozygosity mapping, we identified two families, each with three affected siblings sharing large overlapping homozygous regions that harbored the IMPG2 gene on chromosome 3. Sequence analysis of IMPG2 in the two index cases revealed homozygous mutations cosegregating with the disease in the respective families: three affected siblings of Iraqi Jewish ancestry displayed a nonsense mutation, and a Dutch family displayed a 1.8 kb genomic deletion that removes exon 9 and results in the absence of seven amino acids in a conserved SEA domain of the IMPG2 protein. Transient transfection of COS-1 cells showed that a construct expressing the wild-type SEA domain is properly targeted to the plasma membrane, whereas the mutant lacking the seven amino acids appears to be retained in the endoplasmic reticulum. Mutation analysis in ten additional index cases that were of Dutch, Israeli, Italian, and Pakistani origin and had homozygous regions encompassing IMPG2 revealed five additional mutations; four nonsense mutations and one missense mutation affecting a highly conserved phenylalanine residue. Most patients with IMPG2 mutations showed an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity. The patient with the missense mutation, however, was diagnosed with maculopathy. The IMPG2 gene encodes the interphotoreceptor matrix proteoglycan IMPG2, which is a constituent of the interphotoreceptor matrix. Our data therefore show that mutations in a structural component of the interphotoreceptor matrix can cause arRP.
| S-EPMC2917719 | biostudies-literature
Project description:Photoreceptor neurons are surrounded by an extracellular matrix, called the interphotoreceptor matrix (IPM). Activities crucial to vision occur within the IPM, including trafficking of nutrients and metabolites, retinal attachment, and interactions needed for normal outer segment phagocytosis. The IPM includes the following two unique proteoglycans: IPM proteoglycan 1 (IMPG1) and IMPG2. Patients with mutations in IMPG1/IMPG2 develop visual deficits with subretinal material accumulation, highlighting the critical role of the IPM in vision. To determine the role of these proteoglycans in retinal physiology and the pathologic mechanisms that lead to vision loss, we generated mouse models lacking IMPG1/IMPG2. In normal retina, IMPG1 and IMPG2 occupy distinct IPM compartments, represent the main source of chondroitin sulfate and are fundamental for the constitution of the cone-specific glycocalyx stained by the PNA (peanut agglutinin) lectin marker. No evident morphologic or functional deficits were found in mice lacking IMPG1. In the absence of IMPG2, IMPG1 abnormally accumulated at the subretinal space need, likely leading to the formation of subretinal lesions and reduced visual function. Interestingly, mice lacking both IMPG1 and IMPG2, regardless of sex, showed normal retinal structure and function, demonstrating that the aberrant IMPG1 distribution is the main cause of the visual alterations observed in the absence of IMPG2. In conclusion, our results show the dependence of secreted proteoglycans such as IMPG1 on the extracellular environment to properly integrate into the matrix, demonstrate the role of IMPG2 in shaping the IPM, and shed light on the potential mechanisms leading to the development of subretinal lesions and vision loss.SIGNIFICANCE STATEMENT The photoreceptors are specialized neurons that drive phototransduction in the mammalian retina. These cells are organized and surrounded by an extracellular matrix, the interphotoreceptor matrix (IPM). Mutations in IPM proteoglycans are associated with blindness in humans. Our studies show that two specific proteoglycans of the IPM, IPM proteoglycan 1 (IMPG1) and IMPG2, form a dynamic structure with distinct localization and dependency. When IMPG2 is absent, IMPG1 cannot integrate into the IPM, leading to abnormal proteoglycan accumulation and visual deficits. This work adds a new layer of understanding to IPM physiology and describes the pathologic events following deficits in proteoglycans, providing novel possibilities for visual restoration in patients with IMPG-related pathologies.
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Project description:Cones are critically dependent on interphotoreceptor retinoid-binding protein (IRBP) for retinoid delivery in the visual cycle. Cone-dominant vertebrates offer an opportunity to uncover the molecular basis of IRBP's role in this process. Here, we explore the association of IRBP with the interphotoreceptor matrix (IPM) of cones vs. rods in cone dominant retinas from chicken (Gallus domesticus), turkey (Meleagris gallopavo), and pig (Sus scrofa). Retinas were detached and fixed directly or washed in saline prior to fixation. Disassociated photoreceptors with adherent matrix were also prepared. Under 2 mM CaCl(2) , insoluble matrix was delaminated from saline washed retinas. The distribution of IRBP, as well as glycans binding peanut agglutinin (cone matrix) and wheat germ agglutinin (rod/cone matrix), was defined by confocal microscopy. Retina flat mounts showed IRBP diffusely distributed in an interconnecting, lattice-like pattern throughout the entire matrix. Saline wash replaced this pattern with fluorescent annuli surrounding individual cone outer segments. In isolated cones and matrix sheets, IRBP colocalized with the peanut agglutinin binding matrix glycans. Our results reveal a wash-resistant association of IRBP with a matrix domain immediately surrounding cone outer segments. The cone matrix sheath may be responsible for IRBP-mediated cone targeting of 11-cis retinoids.
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Project description:The pericellular matrix is a robust, hyaluronan-rich polymer brush-like structure that controls access to the cell surface, and plays an important role in cell adhesion, migration, and proliferation. We report the observation of single bottlebrush proteoglycan dynamics in the pericellular matrix of living chondrocytes. Our investigations show that the pericellular matrix undergoes gross extension on the addition of exogenous aggrecan, and that this extension is significantly in excess of that observed in traditional particle exclusion assays. The mean-square displacement of single, bound proteoglycans increases with distance to cell surface, indicating reduced confinement by neighboring hyaluronan-aggrecan complexes. This is consistent with published data from quantitative particle exclusion assays that show openings in the pericellular matrix microstructure ranging from ?150 nm near the cell surface to ?400 nm near the cell edge. In addition, the mobility of tethered aggrecan drops significantly when the cell coat is enriched with bottlebrush proteoglycans. Single-molecule imaging in this thick polysaccharide matrix on living cells has significant promise in the drive to elucidate the role of the pericellular coat in human health.
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Project description:PurposeTo assess the concentrations of matrix metalloproteinase (MMP)-1 and MMP-9 in the aqueous humor of diabetic macular edema (DME) patients.MethodThe concentrations of MMP-1 and MMP-9 in the aqueous humors of 15 cataract patients and 25 DME patients were compared. DME patients were analyzed according to the diabetic retinopathy (DR) stage, diabetes mellitus (DM) duration, pan-retinal photocoagulation (PRP) treatment, recurrence within 3 months, HbA1C (glycated hemoglobin) level, and axial length.ResultsThe concentrations of MMP-1 and MMP-9 of the DME groups were higher than those of the control group (p = 0.005 and p = 0.002, respectively). There was a significant difference in MMP-1 concentration between the mild non-proliferative diabetic retinopathy (NPDR) group and the proliferative diabetic retinopathy (PDR) group (p = 0.012). MMP-1 concentrations were elevated in PRP-treated patients (p = 0.005). There was a significant difference in MMP-9 concentrations between the mild NPDR group and the PDR group (p < 0.001), and between the moderate and severe NPDR group and the PDR group (p < 0.001). The MMP-9 concentrations in PRP treated patients, DM patients with diabetes ≥ 10 years and recurrent DME within 3months were elevated (p = 0.023, p = 0.011, and p = 0.027, respectively). In correlation analyses, the MMP-1 level showed a significant correlation with age (r = -0.48, p = 0.01,), and the MMP-9 level showed significant correlations with axial length (r = -0.59, p < 0.01) and DM duration (r = 049, p = 0.01).ConclusionsConcentrations of MMP-1 and MMP-9 were higher in the DME groups than in the control group. MMP-9 concentrations also differed depending on DR staging, DM duration, PRP treatment, and degree of axial myopia. MMP-9 may be more important than MMP-1 in the induction of DM complications in eyes.
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Project description:PurposeTo characterize mutations within the carbohydrate sulfotransferase 6 (CHST6) gene in Iranian subjects from 12 families with macular corneal dystrophy (MCD).MethodsGenomic DNA was extracted from peripheral blood of 20 affected patients and 60 healthy volunteers followed by polymerase chain reaction (PCR) and direct sequencing of the CHST6 coding region. The observed nucleotide sequences were then compared with those found by investigators in other populations with MCD and in the controls.ResultsAnalysis of CHST6 revealed 11 different mutations. These mutations were comprised of six novel missense mutations (p.F55L, p.P132L, p.S136G, p.C149Y, p.D203Y, and p.H249R), one novel nonsense mutation (p.S48X), one novel frame shift (after P297), and three previously reported missense mutations (p.P31L, p.C165Y, and p.R127C). The majority of the detected MCD mutations are located in the binding sites or the binding pocket, except the p.P31L and p.H249R mutations.ConclusionsNucleotide changes within the coding region of CHST6 are predicted to significantly alter the encoded sulfotransferase within the evolutionary conserved sequences. Our findings show that CHST6 mutations are responsible for the pathogenesis of MCD in Iranian patients. Moreover, the observation that some cases of MCD cannot be explained by mutations in the coding region of CHST6 suggests that MCD may result from possible upstream rearrangements in the CHST6 genomic region.
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Project description:Interphotoreceptor retinol-binding protein (IRBP), the major protein component of the subretinal space, is in a strategic position to mediate cellular interactions between the retinal pigmented epithelium (RPE) and the neural retina. While IRBP appears to be involved in vitamin A transport during the visual cycle in the adult, the role of this protein during eye development has not been determined. As a first step to understanding the role of IRBP during retinal development, we have studied the expression of the mRNA for this glycolipoprotein during photoreceptor differentiation in the rat. A rat neural retina cDNA library was prepared from which an IRBP clone was isolated. The clone contains an open reading frame followed by a 3' noncoding sequence ending in 10 adenosine residues. The coding region has an identity of 83.9 and 82.5% with the nucleotide sequence of human and bovine IRBP, respectively. Rats (Sprague-Dawley, Wistar, and Royal College of Surgeon pink-eyed controls) have a 6.4 and a 5.2-kb mRNA for IRBP which are present in a 1:4 ratio and thus are the only vertebrate known to definitely have more than one major form of the IRBP message. Genomic Southern blots are consistent with the hypothesis that there is only one allele of the IRBP gene, suggesting that the two forms are produced by alternative processing of the mRNA. To generate an antisense RNA probe for use in molecular titration assays and Northern blots, an Eco RI-Bam HI fragment from the coding region was subcloned in between flanking Sp6 and T7 promoters. Total RNA was prepared from undissected rat globes from postnatal days p0-p22. The expression of the mRNA for IRBP was studied by Northern blots and the level of the transcripts determined by solution hybridization assays. Approximately 10(5) IRBP mRNA transcripts/micrograms total eye RNA are present at birth. This increases to a final level of 3.1 X 10(6) transcripts/micrograms total RNA by p9. The one-half maximal level of the mRNA occurs at p4.2 which is 2 wk before the one-half maximal level of IRBP is reached in the subretinal space (Gonzalez-Fernandez, F., R. A. Landers, P. A. Glazebrook, S.-L. Fong, G. I. Liou, D. M. K. Lam, and C. D. B. Bridges. 1984. J. Cell Biol. 99:2092-2098). The expression of the mRNA for IRBP reflects the developmental emergence of the interphotoreceptor matrix as an important structure within the retina.(ABSTRACT TRUNCATED AT 400 WORDS)
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Project description:The extracellular matrix (ECM) is a complex mixture composed of fibrillar collagens as well as additional protein and carbohydrate components. Proteoglycans (PGs) contribute to the heterogeneity of the ECM and play an important role in its structure and function. While the small leucine rich proteoglycans (SLRPs), including decorin and lumican, have been studied extensively as mediators of collagen fibrillogenesis and organization, the function of large matrix PGs in collagen matrices is less well known. In this study, we showed that different matrix PGs have distinct roles in regulating collagen behaviors. We found that versican, a large chondroitin sulfate PG, promotes collagen fibrillogenesis in a turbidity assay and upregulates cell-mediated collagen compaction and reorganization, whereas aggrecan, a structurally-similar large PG, has different and often opposing effects on collagen. Compared to versican, decorin and lumican also have distinct functions in regulating collagen behaviors. The different ways in which matrix PGs interact with collagen have important implications for understanding the role of the ECM in diseases such as fibrosis and cancer, and suggest that matrix PGs are potential therapeutic targets.
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Project description:Background Dilated cardiomyopathy (DCM) is a common cause of heart failure in adult and pediatric patients, but the underlying mechanism may vary in adults and children, with few studies conducted to date. The objective of the present study was to determine whether differential remodeling of the extracellular matrix contributes to the differences between pediatric and adult DCM hearts. Methods and Results Explanted hearts were procured from adult (age, 46-61 years) and pediatric (age, 2-8) patients with DCM-related heart failure and nonfailing control hearts. Fibrillar and nonfibrillar extracellular matrix (proteoglycans, glycosaminoglycans, glycoprotein), their regulatory enzymes (matrix metalloproteinases, disintegrin and metalloproteinases, and disintegrin and metalloproteinases with a thrombospondin domain), and their inhibitors (tissue inhibitor of metalloproteinases) were assessed. Pediatric DCM hearts exhibited less fibrosis compared with adult DCMs. Total glycosaminoglycans increased similarly in both DCM groups but exhibited a significantly lower affinity for transforming growth factor-β in adult DCMs versus pediatric DCMs, resulting in increased bioavailability of transforming growth factor-β1 and a significantly higher activity of the Smad2/3 pathway in adult DCMs. Glycosylated biglycan and versican, and cleaved thrombospondin-1 increased in both DCMs. Protein expression of disintegrin and metalloproteinases with thrombospondin domains (-1, -2, -4, -7) and disintegrin and metalloproteinases (-12, -15, -17, -19) were altered differently in pediatric and adult control and failing hearts. Total matrix metalloproteinase activity increased in both DCMs. Tissue inhibitor of metalloproteinase levels were altered similarly with heart failure in both age groups, and only tissue inhibitor of metalloproteinase 3 decreased in both DCM groups. Conclusions Differential remodeling of glycosaminoglycans in pediatric DCMs versus adult DCMs could underlie the enhanced activation of the transforming growth factor-β pathway, leading to more fibrosis in adult DCM hearts. The distinct remodeling of the fibrillar and nonfibrillar extracellular matrix between pediatric and adult DCM hearts highlights a distinct pathophysiological basis for these cohorts.
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Project description:Age-related macular degeneration (AMD) is a complex, multifactorial and progressive retinal disease affecting millions of people worldwide. In developed countries, it is the leading cause of vision loss and legal blindness among the elderly. Although the pathogenesis of AMD is still barely understood, recent studies have reported that disorders in the regulation of the extracellular matrix (ECM) play an important role in its etiopathogenesis. The dynamic metabolism of the ECM is closely regulated by matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). The present review focuses on the crucial processes that occur at the level of the Bruch's membrane, with special emphasis on MMPs, TIMPs, and the polymorphisms associated with increased susceptibility to AMD development. A systematic literature search was performed, covering the years 1990-2020, using the following keywords: AMD, extracellular matrix, Bruch's membrane, MMPs, TIMPs, and MMPs polymorphisms in AMD. In both early and advanced AMD, the pathological dynamic changes of ECM structural components are caused by the dysfunction of specific regulators and by the influence of other regulatory systems connected with both genetic and environmental factors. Better insight into the pathological role of MMP/TIMP complexes may lead to the development of new strategies for AMD treatment and prevention.
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