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Altered Protein Function Caused by AMD-associated Variant rs704 Links Vitronectin to Disease Pathology.

ABSTRACT: Purpose:Vitronectin, a cell adhesion and spreading factor, is suspected to play a role in the pathogenesis of age-related macular degeneration (AMD), as it is a major component of AMD-specific extracellular deposits (e.g., soft drusen, subretinal drusenoid deposits). The present study addressed the impact of AMD-associated non-synonymous variant rs704 in the vitronectin-encoding gene VTN on vitronectin functionality.

Methods:Effects of rs704 on vitronectin expression and processing were analyzed by semi-quantitative sequencing of VTN transcripts from retinal pigment epithelium (RPE) cells generated from human induced pluripotent stem cells (hiPSCs) and from human neural retina, as well as by western blot analyses on heterologously expressed vitronectin isoforms. Binding of vitronectin isoforms to retinal and endothelial cells was analyzed by western blot. Immunofluorescence staining followed extracellular matrix (ECM) deposition in cultured RPE cells heterologously expressing the vitronectin isoforms. Adhesion of fluorescently labeled RPE or endothelial cells in dependence of recombinant vitronectin or vitronectin-containing ECM was investigated fluorometrically or microscopically. Tube formation and migration assays addressed effects of vitronectin on angiogenesis-related processes.

Results:Variant rs704 affected expression, secretion, and processing but not oligomerization of vitronectin. Cell binding and influence on RPE-mediated ECM deposition differed between AMD-risk-associated and non-AMD-risk-associated protein isoforms. Finally, vitronectin affected adhesion and endothelial tube formation.

Conclusions:The AMD-risk-associated vitronectin isoform exhibits increased expression and altered functionality in cellular processes related to the sub-RPE aspects of AMD pathology. Although further research is required to address the subretinal disease aspects, this initial study supports an involvement of vitronectin in AMD pathogenesis.

SUBMITTER: Biasella F

PROVIDER: S-EPMC7718807 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Altered Protein Function Caused by AMD-associated Variant rs704 Links Vitronectin to Disease Pathology.

Biasella Fabiola F Plössl Karolina K Karl Claudia C Weber Bernhard H F BHF Friedrich Ulrike U

Investigative ophthalmology & visual science 20201201 14

<h4>Purpose</h4>Vitronectin, a cell adhesion and spreading factor, is suspected to play a role in the pathogenesis of age-related macular degeneration (AMD), as it is a major component of AMD-specific extracellular deposits (e.g., soft drusen, subretinal drusenoid deposits). The present study addressed the impact of AMD-associated non-synonymous variant rs704 in the vitronectin-encoding gene VTN on vitronectin functionality.<h4>Methods</h4>Effects of rs704 on vitronectin expression and processin ...[more]

PMID: 33259607

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Project description:Age related macular degeneration is a disease which occurs in aged individuals. There are various changes that occur at the cellular, molecular and physiological level with advancing age (Samiec et al., 1988; Sharma K. et al., 2014). Drusen deposition between retinal pigment epithelium (RPE) and Bruch's membrane (BM) is one of the key features in AMD patients (Mullins et al., 2000; Hageman et al., 2001) similar to A?/tau aggregates in Alzheimer's disease (AD) patients. The primary goal of this review is to discuss whether the various candidate genes and associated biomarkers, that are known to play an independent role in progression of AMD, exert deleterious effect on phenotype, alone or in combination, in Indian AMD patients from the same ethnic group and the significance of such research. A statistical model for probable interaction between genes could be derived from such analysis. Therefore, one can use multiple modalities to identify and enrol AMD patients based on established clinical criteria and examine the risk factors to determine if these genes are associated with risk factors, biomarkers or disease by Mendelian randomization. Similarly, there are large numbers of single nucleotide polymorphisms (SNPs) identified in human population. Even non-synonymous SNPs (nsSNPs) are believed to induce deleterious effects on the functionality of various proteins. The study of such snSNPs could provide a better genetic insight for diverse phenotypes of AMD patients, predicting significant risk factors for the disease in Indian population. Therefore, the prediction of biological effect of nsSNPs in the candidate genes and the associated grant applications in the subject are highly solicited.Therefore, genotyping and levels of protein expression of various genes would provide wider canvas in genetic complexity of AMD pathology which should be evaluated by valid statistical and bioinformatics' tools. Longitudinal follow up of Indian AMD patients to evaluate the temporal effect of SNPs and biomarkers on progression of disease would provide a unique strategy in the field.

Dataset Information

Altered Protein Function Caused by AMD-associated Variant rs704 Links Vitronectin to Disease Pathology.

Publications

Altered Protein Function Caused by AMD-associated Variant rs704 Links Vitronectin to Disease Pathology.

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