Cadherin 5 is Regulated by Corticosteroids and Associated with Central Serous Chorioretinopathy

Schubert, Carl; Pryds, Anders; Zeng, Siyuan; Xie, Yajing; Freund, K. Bailey; Spaide, Richard F.; Merriam, John C.; Barbazetto, Irene; Slakter, Jason S.; Chang, Stanley; Munch, Inger Christine; Drack, Arlene V.; Hernández, Javier; Yzer, Suzanne; Merriam, Joanna E.; Linneberg, Allan; Larsen, Michael; Yannuzzi, Lawrence A.; Mullins, Robert F.; Allikmets, Rando

doi:10.1002/humu.22551

Cited by 91 publications

(80 citation statements)

References 38 publications

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“…The genetic cause of CSC is largely unknown. Variants in the CDH5 gene, currently the only gene reliably associated with the CSC phenotype (Schubert et al 2014), were not detected in patient I-1. PD, as presented in patient I-2, refers to a group of slowly progressive macular diseases that manifest with minimal diminution of visual acuity and photoreceptor atrophy in older individuals (Marmor and McNamara 1996; Watzke et al 1982).…”

Section: Discussionmentioning

confidence: 91%

Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes

et al. 2015

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Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants (SNV) and copy number variants (CNV) that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes.

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Section: Discussionmentioning

confidence: 91%

Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes

et al. 2015

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“…Transmission electron microscopy was performed as described previously [23]. Briefly, native or decellularized human RPE/choroid tissue samples were collected and allowed to sit in 1/2-strength Karnovsky fixative overnight, followed by osmium tetroxide and uranyl acetate staining.…”

Section: Methodsmentioning

confidence: 99%

Preparation and evaluation of human choroid extracellular matrix scaffolds for the study of cell replacement strategies

et al. 2017

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Endothelial cells (ECs) of the choriocapillaris are one of the first cell types lost during age-related macular degeneration (AMD), and cell replacement therapy is currently a very promising option for patients with advanced AMD. We sought to develop a reliable method for the production of human choroidal extracellular matrix (ECM) scaffolds, which will allow for the study of choroidal EC (CEC) replacement strategies in an environment that closely resembles the native tissue. Human RPE/choroid tissue was treated sequentially with Triton X-100, SDS, and DNase to remove all native cells. While all cells were successfully removed from the tissue, collagen IV, elastin, and laminin remained, with preserved architecture of the acellular vascular tubes. The ECM scaffolds were then co-cultured with exogenous ECs to determine if the tissue can support cell growth and allow EC reintegration into the decellularized choroidal vasculature. Both monkey and human ECs took up residence in the choriocapillary tubes of the decellularized tissue. Together, these data suggest that our decellularization methods are sufficient to remove all cellular material yet gentle enough to preserve tissue structure and allow for the optimization of cell replacement strategies.

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“…Finally, in a cohort of 400 CSCR cases (compared to 1400 matched controls), a significant association was found with 4 common cadherin 5 single-nucleotide polymorphisms in CSCR male patients. Since cadherin 5 contributes to intercellular adhesions in the vascular endothelium, and is down-regulated by corticosteroids, genetic variations in cadherin 5, combined with triggering events such as corticosteroid treatment, could explain a proportion of CSCR occurrences among male patients (Schubert et al, 2014).…”

Section: Genetic Predispositionmentioning

confidence: 99%

Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis

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Dirani

et al. 2015

Progress in Retinal and Eye Research

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Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress.

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Cadherin 5 is Regulated by Corticosteroids and Associated with Central Serous Chorioretinopathy

Cited by 91 publications

References 38 publications

Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes

Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes

Preparation and evaluation of human choroid extracellular matrix scaffolds for the study of cell replacement strategies

Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis

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