Evaluation of NTF4 as a causative gene for primary open-angle glaucoma.
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ABSTRACT:
SUBMITTER: Chen LJ
PROVIDER: S-EPMC3398503 | biostudies-literature | 2012
REPOSITORIES: biostudies-literature
Publications
Evaluation of NTF4 as a causative gene for primary open-angle glaucoma.
Chen Li Jia LJ Ng Tsz Kin TK Fan Alex H AH Leung Dexter Y L DY Zhang Mingzhi M Wang Ningli N Zheng Yuqian Y Liang Xiao Ying XY Chiang Sylvia W Y SW Tam Pancy O S PO Pang Chi Pui CP
Molecular vision 20120628
<h4>Purpose</h4>The neurotrophin-4 (NTF4) gene has been recently implicated in primary open-angle glaucoma (POAG). In this study, we investigated the implication of NTF4 in POAG among three Chinese cohorts.<h4>Methods</h4>The coding regions and exon-intron boundaries of NTF4 was sequenced in 950 unrelated Chinese subjects, including a Hong Kong cohort of 390 patients and 230 controls, a Shantou cohort of 130 patients, and a Beijing cohort of 200 patients. Constructs carrying the detected variant ...[more]
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Project description:Glaucoma, a main cause of blindness in the developed world, is characterized by progressive degeneration of retinal ganglion cells (RGCs), resulting in irreversible loss of vision. Although members of the neurotrophin gene family in various species are known to support the survival of numerous neuronal populations, including RGCs, it is less clear whether they are also required for survival and maintenance of adult neurons in humans. Here, we report seven different heterozygous mutations in the Neurotrophin-4 (NTF4) gene accounting for about 1.7% of primary open-angle glaucoma patients of European origin. Molecular modeling predicted a decreased affinity of neurotrophin 4 protein (NT-4) mutants with its specific tyrosine kinase receptor B (TrkB). Expression of recombinant NT-4 carrying the most frequent mutation was demonstrated to lead to decreased activation of TrkB. These findings suggest a pathway in the pathophysiology of glaucoma through loss of neurotrophic function and may eventually open the possibility of using ligands activating TrkB to prevent the progression of the disease.
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Project description:Neurotrophin-4 protein (NT-4) plays a role in the protection of retinal ganglion cells by activating tyrosine kinase B (TrkB) receptors. A recent study identified mutations within the neurotrophin-4 (NTF4) gene to account for 1.7% of primary open-angle glaucoma (POAG) in Europeans. The aim of this study was to investigate the frequency of NTF4 mutations in Chinese POAG patients.One hundred-seventy-four Chinese subjects with POAG and 91 normal Chinese subjects were recruited. POAG was defined by the presence of glaucomatous optic neuropathy, open angles on gonioscopy, and absence of secondary causes of glaucoma. The single coding exon of NTF4 was PCR amplified and subjected to bidirectional sequencing in all subjects.The mean age of POAG patients was 66.0+/-13.0 years (range 25-96 years) and that of controls was 67.1+/-4.6 years (range 60-85 years). We identified a novel NTF4 missense mutation substituting leucine by serine at codon 113 (Leu113Ser) caused by a c.338T>C mutation in a single patient with unilateral POAG, who presented with a baseline intraocular pressure of 25 mmHg, a vertical cup-to-disc ratio of 0.9 and an inferior hemifield defect in the affected eye. Structural analysis indicated that the Leu113Ser mutation is likely to alter the NT-4 protein structure near the TrkB binding site and disrupts the formation of the NT-4-TrkB complex required for the activation of TrkB.Identification of a single mutation in our study suggests that NTF4 mutations are a rare cause of POAG (0.6%, 95%CI 0.02%-3.16%) in Chinese people.
| S-EPMC2927376 | biostudies-literature
Project description:A substantial fraction of glaucoma has a genetic basis. About 5% of primary open angle glaucoma (POAG) is currently attributed to single-gene or Mendelian forms of glaucoma (ie glaucoma caused by mutations in myocilin or optineurin). Mutations in these genes have a high likelihood of leading to glaucoma and are rarely seen in normal subjects. Other cases of POAG have a more complex genetic basis and are caused by the combined effects of many genetic and environmental risk factors, each of which do not act alone to cause glaucoma. These factors are more frequently detected in patients with POAG, but are also commonly observed in normal subjects. Additional genes that may be important in glaucoma pathogenesis have been investigated using quantitative traits approaches. Such studies have begun to identify genes that control the magnitude of important quantitative features of glaucoma that may also be important risk factors for POAG, such as central corneal thickness. Each of these different approaches to study glaucoma genetics is providing new insights into the pathogenesis of POAG.
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Project description:AimTo estimate the risk of blindness with primary angle-closure glaucoma (PACG) compared to primary open-angle glaucoma (POAG) in those population-based studies that reported blindness rates for both PACG and POAG.MethodA systematic search was performed in PubMed for articles published in English between 2000 and 2020 reporting the prevalence of POAG as well as PACG among various ethnic populations. A study was included if it was (1) population-based (2) had published prevalence and blindness rates for both PACG and POAG in the same cohort. (3) Glaucoma was defined as per the International Society for Geographical and Epidemiological Ophthalmology (ISGEO) criteria. The proportion of blindness for both POAG and PACG for each study and the cumulative proportion taking all the studies were calculated.ResultsWe included 23 studies with 78,434 participants. POAG was diagnosed in 1702 persons with 151 (8.9%) blind. There were 724 cases of PACG with 196 (27.0%) blind. The risk ratio of blindness in PACG to POAG varied from 0.73 to 10.6 among the studies. The cumulative risk ratio was 2.39 (95% confidence interval (CI); 1.99, 2.87). Risk ratios for studies including visual field restriction while defining blindness were similar to studies that did not (1.92 vs 2.64, P = 0.11). Risk ratios were also similar for studies that used greater than 2 instead of 3 or more quadrants of iridotrabecular contact to define angle closure (2.79 vs 2.25).ConclusionPrimary angle-closure disease is more likely to be associated with blindness.
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Project description:BackgroundWe investigated the molecular basis of primary open-angle glaucoma (POAG) using Opticin (OPTC) as a candidate gene on the basis of its expression in the trabecular meshwork cells involved in the disease pathogenesis. Two hundred POAG patients and 100 controls were enrolled in this study. The coding sequence of OPTC was amplified by PCR from genomic DNA of POAG patients, followed by SSCP, DHPLC and DNA sequencing. Subsequent bioinformatic analysis, site-directed mutagenesis, quantitative RT-PCR and western blot experiments were performed to address the functional significance of a 'silent' change in the OPTC coding region while screening for mutations in POAG patients.ResultsWe detected two missense (p.Glu66Gly & p.Ile89Thr) and one silent change (p.Phe162Phe; c.602 C>T) that was present in 3 different patients but in none of the 100 controls screened. The mutant (c.602T) mRNA was predicted to have remarkably different secondary structure compared to the wild-type transcript by in silico approaches. Subsequent wet-lab experiments showed lower expression of the gene both at the mRNA and protein levels.ConclusionOur study suggests OPTC as a candidate gene for POAG. Further, it highlights the importance of investigating the 'silent' variations for functional implication that might not be apparent from only in silico analysis.
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2008-06-12 | E-GEOD-2387 | biostudies-arrayexpress
Project description:BACKGROUND:Recently nonsynonymous coding variants in the ankyrin repeats and suppressor of cytokine signaling box-containing protein 10 (ASB10) gene were found to be associated with primary open angle glaucoma (POAG) in cohorts from Oregon and Germany, but this finding was not confirmed in an independent cohort from Iowa. The aim of the current study was to assess the role of ASB10 gene variants in Pakistani glaucoma patients. METHODS:Sanger sequencing of the coding exons and splice junctions of the ASB10 gene was performed in 30 probands of multiplex POAG families, 208 sporadic POAG patients and 151 healthy controls from Pakistan. Genotypic associations of individual variants with POAG were analyzed with the Fisher's exact or Chi-square test. RESULTS:In total 24 variants were identified in POAG probands and sporadic patients, including 11 novel variants and 13 known variants. 13 of the variants were nonsynonymous, 6 were synonymous, and 5 were intronic. Three nonsynonymous variants (p.Arg49Cys, p.Arg237Gly, p.Arg453Cys) identified in the probands were not segregating in the respective families. This is not surprising since glaucoma is a multifactorial disease, and multiple factors are likely to be involved in the disease manifestation in these families. However a nonsynonymous variant, p.Arg453Cys (rs3800791), was found in 6 sporadic POAG patients but not in controls, suggesting that it infers increased risk for the disease. In addition, one synonymous variant was found to be associated with sporadic POAG: p.Ala290Ala and the association of the variant with POAG remained significant after correction for multiple testing (uncorrected p-value 0.002, corrected p-value 0.047). The cumulative burden of rare, nonsynonymous variants was significantly higher in sporadic POAG patients compared to control individuals (p-value 0.000006). CONCLUSIONS:Variants in ASB10 were found to be significantly associated with sporadic POAG in the Pakistani population. This supports previous findings that sequence variants in the ASB10 gene may act as a risk factor for glaucoma.
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Project description:Glaucoma is a genetically heterogeneous disorder and is the second cause of blindness worldwide owing to the progressive degeneration of retinal ganglion neurons. Very few genes causing glaucoma were identified to this date. In this study, we screened 10 candidate genes of glaucoma between the D14S261 and D14S121 markers of chromosome 14q11, a critical region previously linked to primary open-angle glaucoma (POAG). Mutation analyses of two large cohorts of patients with POAG, normal tension glaucoma (NTG) and juvenile open-angle glaucoma (JOAG), and control subjects, found only association of non-synonymous heterozygous variants of the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) with POAG, NTG and JOAG. The 20 non-synonymous variants identified in RPGRIP1 were all distinct from variants causing photoreceptor dystrophies and were found throughout all but one domain (RPGR-interacting domain) of RPGRIP1. Among them, 14 missense variants clustered within or around the C2 domains of RPGRIP1. Yeast two-hybrid analyses of a subset of the missense mutations within the C2 domains of RPGRIP1 shows that five of them (p.R598Q, p.A635G, p.T806I, p.A837G and p.I838V) decrease the association of the C2 domains with nephrocystin-4 (NPHPH). When considering only these five confirmed C2-domain mutations, the association remains statistically significant (P=0.001). Altogether, the data support that heterozygous non-synonymous variants of RPGRIP1 may cause or increase the susceptibility to various forms of glaucoma and that among other factors, physical impairment of the interaction of RPGRIP1with different proteins may contribute to the pathogenesis of forms of glaucoma.
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Project description:Glaucoma is known to induce visual impairment and blindness. The aim of the present study was to determine the clinical and genetic findings of a family with primary open-angle glaucoma (POAG). A family diagnosed with glaucoma was examined clinically and followed up for five years. Genomic DNA was extracted from the venous blood of 12 family members, and of 100 healthy individuals. The mode of inheritance was determined by the pedigree analysis. The third exon and its flanking introns of myocilin (MYOC) were amplified, and quantitative polymerase chain reaction (qPCR) products were sequenced. The restriction fragment length polymorphism analysis was performed on samples from the 12 family members and 100 normal controls. The predicted effects of the detected variants on the secondary structure of the MYOC protein were analyzed by the Garnier-Osguthorpe-Robson method. In this family, three members were diagnosed with POAG, and one member with ocular hypertension. The mode of inheritance of the family was autosomal dominant with six members being genetically affected. The heterozygous mutation was identified in the third exon of MYOC that revealed a T → C transition at position 1021 (p.S341P), which switched serine (Ser) to proline (Pro). This is a missense mutation eliminating a CviKI-1 restriction site that segregated the affected members. Secondary structure prediction of p.S341P suggested that the MYOC protein was misfolded. Ser341Pro MYOC mutation was detected in the family with POAG. The clinical and genetic characteristics of this mutation require further investigation. The mutation spectrum of MYOC may be expanded for a better diagnosis and treatment for POAG patients.
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Project description:This study aimed to investigate the molecular mechanism responsible for primary open-angle glaucoma (POAG) progression. We analyzed microRNAs (miRNAs) expression profiling in aqueous humor (AH) of both POAG patients and normal controls, using a microarray-based approach. Subsequently, differentially expressed miRNAs (DEmiRNAs) were identified using Bayes moderated t-test. Next, DEmiRNAs target genes were predicted based on miRNA databases, followed by GO analysis and pathway analysis using DAVID. Furthermore, OAG-related genes analysis for target genes was carried out using CTD database, respectively. Finally, verification of DEmiRNAs expression levels was performed by RT-qPCR. A total of 40 significant DEmiRNAs were identified between control and POAG groups, including 24 up-regulated miRNAs and 16 down-regulated miRNAs. Further, the target genes of hsa-miR-206, including BMP2, SMAD4, ID2, and TNF, were mainly enriched in transforming growth factor-β (TGF-β) signaling pathway. While, target genes of hsa-miR-184, hsa-miR-34c-5p, hsa-miR-7-2-3p and hsa-miR-20b-3p, including BCL2, EPHB2, VEGFA, COL4A1, APC, and TGFBR1, were enriched in eye development. Moreover, FNDC3B, CAV2 and VEGF, target genes of hsa-miR-206 or hsa-miR-34c-5p, were the OAG-related genes. Ultimately, RT-qPCR analysis confirmed that mRNA levels of hsa-miR-206, hsa-miR-7-2-3p, and hsa-miR-20b-3p were increased, while those of hsa-miR-184 and hsa-miR-34c-5p were decreased in POAG compared with normal groups (P < 0.05). Hsa-miR-206, hsa-miR-184, hsa-miR-34c-5p, hsa-miR-7-2-3p and hsa-miR-20b-3p might play a significant role in the pathogenesis of POAG and hsa-miR-206 might be associated with the development of POAG by regulating TGF-β signaling pathway. These results might provide insight toward a better understanding of the pathogenesis of POAG.
2015-08-04 | GSE71639 | GEO