Overexpression of HTRA1 Leads to Down-Regulation of Fibronectin and Functional Changes in RF/6A Cells and HUVECs

Jiang, Jingjing; Huang, Lvzhen; Yu, Wenzhen; Wu, Xi; Zhou, Peng; Li, Xiaoxin

doi:10.1371/journal.pone.0046115

Cited by 18 publications

(17 citation statements)

References 43 publications

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“…Our findings support the idea that HtrA1 keeps IGF-1 levels in check and therefore regulates angiogenic homeostasis (69). Furthermore, if this function is compromised, as is the case in patients harboring dSNPs, the balance shifts to favor angiogenesis and thereby permits the accumulation of the choroidal neovessels.…”

Section: Discussionsupporting

confidence: 86%

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Jacobo

DeAngelis

Kim

et al. 2013

Molecular and Cellular Biology

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Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular agerelated macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD. Single nucleotide polymorphisms (SNPs) that fall within the coding region have the potential to alter the amino acid sequence of a gene's product and therefore can serve as a Rosetta stone for understanding the pathogenesis of human disorders (1, 2). A curiosity that emerged from human genome-wide association studies is that exonic SNPs that do not alter the amino acid sequence of the protein product (i.e., SNPs that are synonymous) are as common as SNPs that do (i.e., SNPs that are nonsynonymous) (3). Furthermore, some of the disease-associated synonymous SNPs constitute the molecular underpinnings of pathology, meaning that they are enriched in affected human subjects and alter the gene product. For the majority (95%) of disease-associated synonymous SNPs, aberrant gene products were attributed to unstable mRNA transcripts with a reduced half-life or mutations in splice sites that resulted in exon skipping (4, 5). In other cases, synonymous SNPs caused translational defects independently of mRNA splicing errors (6-9).A parsimonious mechanism by which synonymous SNPs impact the integrity of protein products involves the alteration of codon usage. In vivo, folding of nascent proteins proceeds cotranslationally (10, 11) and is influenced by the rate of ribosome transit through the mRNA template. What distinguishes synonymous codons that encode a given degenerate amino acid is the abundance of their corresponding tRNA, which is lower for infrequently used codons than for frequently used codons (12, 13). Consequently, codon frequency can influence the rate of translation. Of note, codon bias has been widely described in prokaryotes and single-celled eukaryotes but less extensively in complex eukaryotes.In humans, correlations between optimum codon usage and either protein expression...

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Section: Discussionsupporting

confidence: 86%

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Jacobo

DeAngelis

Kim

et al. 2013

Molecular and Cellular Biology

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“…() support the idea that HTRA1 keeps IGF1 levels in check and therefore regulates angiogenic homoeostasis (Jiang et al. ). HtrA serine peptidase 1 ( HTRA1 ) overexpression in the RPE may serve as an IGF1 sink and therefore may compromise photoreceptor and choriocapillary survival.…”

Section: Chronic Hyperglycaemiasupporting

confidence: 69%

Diabetic macular oedema: under‐represented in the genetic analysis of diabetic retinopathy

Broadgate

Kiire

Halford

et al. 2018

Acta Ophthalmologica

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Diabetic retinopathy, a complication of both type 1 and type 2 diabetes, is a complex disease and is one of the leading causes of blindness in adults worldwide. It can be divided into distinct subclasses, one of which is diabetic macular oedema. Diabetic macular oedema can occur at any time in diabetic retinopathy and is the most common cause of vision loss in patients with type 2 diabetes. The purpose of this review is to summarize the large number of genetic association studies that have been performed in cohorts of patients with type 2 diabetes and published in English-language journals up to February 2017. Many of these studies have produced positive associations with gene polymorphisms and diabetic retinopathy. However, this review highlights that within this large body of work, studies specifically addressing a genetic association with diabetic macular oedema, although present, are vastly under-represented. We also highlight that many of the studies have small patient numbers and that meta-analyses often inappropriately combine patient data sets. We conclude that there will continue to be conflicting results and no meaningful findings will be achieved if the historical approach of combining all diabetic retinopathy disease states within patient cohorts continues in future studies. This review also identifies several genes that would be interesting to analyse in large, well-defined cohorts of patients with diabetic macular oedema in future candidate gene association studies.

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“…The over-expression of these two genes was consistent with this hypothesis. Interestingly, fibronectin mRNA and protein levels were significantly down-regulated following the up-regulation of HTRA1 in rhesus monkey choroid-retina endothelial cells (RF/6A) and human umbilical vein endothelial cells (HUVECs) (Jiang et al , 2012), suggesting that some other unknown factors may be involved in the interaction between HTRA1 and fibronectin in IVD tissues.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profile analysis of human intervertebral disc degeneration

Chen

Zhu

et al. 2013

Genet. Mol. Biol.

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In this study, we used microarray analysis to investigate the biogenesis and progression of intervertebral disc degeneration. The gene expression profiles of 37 disc tissue samples obtained from patients with herniated discs and degenerative disc disease collected by the National Cancer Institute Cooperative Tissue Network were analyzed. Differentially expressed genes between more and less degenerated discs were identified by significant analysis of microarray. A total of 555 genes were significantly overexpressed in more degenerated discs with a false discovery rate of < 3%. Functional annotation showed that these genes were significantly associated with membrane-bound vesicles, calcium ion binding and extracellular matrix. Protein-protein interaction analysis showed that these genes, including previously reported genes such as fibronectin, COL2A1 and β-catenin, may play key roles in disc degeneration. Unsupervised clustering indicated that the widely used morphology-based Thompson grading system was only marginally associated with the molecular classification of intervertebral disc degeneration. These findings indicate that detailed, systematic gene analysis may be a useful way of studying the biology of intervertebral disc degeneration.

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Overexpression of HTRA1 Leads to Down-Regulation of Fibronectin and Functional Changes in RF/6A Cells and HUVECs

Cited by 18 publications

References 43 publications

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Diabetic macular oedema: under‐represented in the genetic analysis of diabetic retinopathy

Gene expression profile analysis of human intervertebral disc degeneration

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