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Peiquan Zhao - One of the best experts on this subject based on the ideXlab platform.
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intravitreal ranibizumab treatment for advanced Familial Exudative Vitreoretinopathy with high vascular activity
2021Co-Authors: Jiao Lyu, Xiang Zhang, Qi Zhang, Ping Fei, Peiquan ZhaoAbstract:PURPOSE To determine the efficacy of intravitreal ranibizumab (IVR) treatment for advanced Familial Exudative Vitreoretinopathy with high vascular activity. METHODS The retrospective interventional case series included 28 eyes (20 patients) that had IVR in combination or not with other treatment, for Stage 3 to 5 Familial Exudative Vitreoretinopathy with active fibrovascular proliferation and prominent subretinal exudation. Outcome measures were fundus features after treatment, associated clinical variables, and genetic mutations. RESULTS The age of patients at the first IVR ranged from 0.2 to 36 months. An average of 1.3 IVR injections per eye were given. Familial Exudative Vitreoretinopathy regressed in 16 (57%) eyes and progressed in 12 eyes (43%) after IVR. Laser and/or vitrectomy was performed on 13 eyes. The retina was reattached in 22 eyes (78%) after 24 to 58 months follow-up. Clinical variables associated with progression after IVR were preexisting fibrovascular proliferation over one quadrant and persistent vascular activity after the initial injection (P < 0.05). Familial Exudative Vitreoretinopathy-causative genetic mutations in 11 patients were related to variable response to IVR treatment. CONCLUSION Intravitreal ranibizumab treatment may effectively regress advanced Familial Exudative Vitreoretinopathy with high vascular activity in selected cases. Different treatment outcomes may be relevant to variable presentation and genetic heterogeneity of Familial Exudative Vitreoretinopathy.
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lamellar macular hole with lamellar hole associated epiretinal proliferation in Familial Exudative Vitreoretinopathy
2021Co-Authors: Jingjing Liu, Peiquan ZhaoAbstract:Purpose To present a clinical case of lamellar macular hole with lamellar hole-associated epiretinal proliferation in a pediatric Familial Exudative Vitreoretinopathy patient. Retinal findings are described, and spectral domain optical coherence tomography documentation is provided. The efficacy of surgical intervention is also discussed. Methods A 4-year-old girl presented with poor vision in her right eye, which was discovered during routine physical examination. Clinical examination revealed Familial Exudative Vitreoretinopathy in both eyes and a lamellar macular hole in the right eye. Both of the patient's parents were also examined, which revealed Familial Exudative Vitreoretinopathy in the girl's father. The patient underwent vitrectomy, inner limiting membrane and lamellar hole-associated epiretinal proliferation peeling, and air-fluid exchange. Results Images obtained with optical coherence tomography revealed lamellar hole-associated epiretinal proliferation at the lamellar defect edge in the patient's right eye. Postoperative examination showed that the lamellar macular hole had closed. Conclusion Pediatric Familial Exudative Vitreoretinopathy patients may develop lamellar macular hole with lamellar hole-associated epiretinal proliferation. Vitreoretinal surgery effectively closes this type of macular hole.
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catenin α 1 mutations cause Familial Exudative Vitreoretinopathy by overactivating norrin β catenin signaling
2021Co-Authors: Xianjun Zhu, Lulin Huang, Yeming Yang, Peiquan Zhao, Mu Yang, Shanshan Zhang, Lin Zhang, Ping Fei, Yi Huang, Ye YuanAbstract:Familial Exudative Vitreoretinopathy (FEVR) is a severe retinal vascular disease that causes blindness. FEVR has been linked to mutations in several genes associated with inactivation of the Norrin/β-catenin signaling pathway, but these account for only approximately 50% of cases. We report that mutations in CTNNA1 (α-catenin) cause FEVR by overactivating the β-catenin pathway and disrupting cell adherens junctions. Three heterozygous mutations in CTNNA1 (p.F72S, p.R376Cfs*27 and p.P893L) were identified by exome-sequencing. We further demon-strated that FEVR-associated mutations led to overactivation of Norrin/β-catenin signaling due to impaired protein interactions within the cadherin/catenin complex. The clinical features of FEVR were reproduced in mice lacking Ctnna1 in vascular endothelial cells (ECs) or with overactivat-ed β-catenin signaling by an EC-specific gain-of-function allele of Ctnnb1. In isolated mouse lung endothelial cells, both CTNNA1-P893L and F72S mutants failed to rescue either the dis-rupted F-ACTIN arrangement or VE-Cadherin and CTNNB1 distribution. Moreover, we discov-ered that compound heterozygous Ctnna1 F72S and a deletion allele could cause similar pheno-type. Furthermore, a LRP5 mutation, which activates Norrin/β-catenin signaling, was identified in a FEVR family and the corresponding knock-in mice exhibited partial FEVR-like phenotype. Our study demonstrates that precise regulation of β-catenin activation is critical for retinal vascu-lar development and provides new insights into the pathogenesis of FEVR.
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catenin alpha 1 mutations cause Familial Exudative Vitreoretinopathy by overactivating norrin beta catenin signaling
2021Co-Authors: Xianjun Zhu, Lulin Huang, Yeming Yang, Peiquan Zhao, Mu Yang, Shanshan Zhang, Lin Zhang, Ping Fei, Yi Huang, Ye YuanAbstract:Familial Exudative Vitreoretinopathy (FEVR) is a severe retinal vascular disease that causes blindness. FEVR has been linked to mutations in several genes associated with inactivation of the Norrin/β-catenin signaling pathway, but these account for only approximately 50% of cases. We report that mutations in CTNNA1 (α-catenin) cause FEVR by overactivating the β-catenin pathway and disrupting cell adherens junctions. Three heterozygous mutations in CTNNA1 (p.F72S, p.R376Cfs*27 and p.P893L) were identified by exome-sequencing. We further demon-strated that FEVR-associated mutations led to overactivation of Norrin/β-catenin signaling due to impaired protein interactions within the cadherin/catenin complex. The clinical features of FEVR were reproduced in mice lacking Ctnna1 in vascular endothelial cells (ECs) or with overactivat-ed β-catenin signaling by an EC-specific gain-of-function allele of Ctnnb1. In isolated mouse lung endothelial cells, both CTNNA1-P893L and F72S mutants failed to rescue either the dis-rupted F-ACTIN arrangement or VE-Cadherin and CTNNB1 distribution. Moreover, we discov-ered that compound heterozygous Ctnna1 F72S and a deletion allele could cause similar pheno-type. Furthermore, a LRP5 mutation, which activates Norrin/β-catenin signaling, was identified in a FEVR family and the corresponding knock-in mice exhibited partial FEVR-like phenotype. Our study demonstrates that precise regulation of β-catenin activation is critical for retinal vascu-lar development and provides new insights into the pathogenesis of FEVR.
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exome sequencing revealed notch ligand jag1 as a novel candidate gene for Familial Exudative Vitreoretinopathy
2020Co-Authors: Lin Zhang, Shujin Li, Lulin Huang, Yeming Yang, Peiquan Zhao, Huijuan Xu, Mu Yang, Shanshan Zhang, Xiang Zhang, Zhenglin YangAbstract:PURPOSE: Familial Exudative Vitreoretinopathy (FEVR) is a blindness-causing retinal vascular disease characterized by incomplete vascularization of the peripheral retina and by the absence or abnormality of the second/tertiary capillary layers in the deep retina. Variants in known FEVR disease genes can only explain about 50% of FEVR-affected cases. We aim to identify additional disease genes in patients with FEVR. METHODS: We applied exome sequencing analysis in a cohort of 49 FEVR families without pathogenic variants in known FEVR genes. Functions of the affected proteins were evaluated by reporter assay. Knockout mouse models were generated by endothelial-specific Cre line. RESULTS: Three novel rare heterozygous variants in Notch ligand JAG1 were identified in FEVR families-c.413C>T p. (A138V), c.1415G>A p. (R472H), and c.2884A>G p. (T962A)-and verified by Sanger sequencing analysis. Notch reporter assay revealed that mutant JAG1 proteins JAG1-A138V and JAG1-T962A lost almost all of their activities, and JAG1-R472H lost approximately 50% of its activity. Deletion of Jag1 in mouse endothelial cells resulted in reduced tip cells at the angiogenic front and retarded vessel growth, reproducing FEVR-like phenotypes. CONCLUSION: Our data suggest that JAG1 is a novel candidate gene for FEVR and pinpoints a potential target for therapeutic intervention.
Michael T. Trese - One of the best experts on this subject based on the ideXlab platform.
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etiology and clinical characteristics of macular edema in patients with Familial Exudative Vitreoretinopathy
2020Co-Authors: Prethy Rao, Yoshihiro Yonekawa, Benjamin J. Thomas, Kimberly A. Drenser, Itsara Lertjirachai, Madeline Hasbrook, Edward H Wood, Neesurg S Mehta, Greta Mane, Michael T. TreseAbstract:Purpose:To describe the etiology and clinical characteristics of macular edema (ME) in patients with Familial Exudative Vitreoretinopathy.Methods:Observational, retrospective case series of 30 patients (34 eyes) with ME and Familial Exudative Vitreoretinopathy who underwent spectral-domain optical c
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Retinal Vascular Tortuosity and Exudative Retinopathy In A Family With Dyskeratosis Congenita Masquerading As Familial Exudative Vitreoretinopathy
2017Co-Authors: Aristomenis Thanos, Yoshihiro Yonekawa, Bozho Todorich, Stephen M Hypes, Benjamin J. Thomas, Sandeep Randhawa, Kimberly A. Drenser, Michael T. TreseAbstract:Purpose To report a novel presentation of dyskeratosis congenita masquerading as Familial Exudative Vitreoretinopathy. Methods Observational case series involving single family and literature review. Results A brother and sister were diagnosed with Familial Exudative Vitreoretinopathy at ages 4 and 2, respectively. Both patients were managed with laser photocoagulation. Eight years after the initial presentation, both siblings developed pancytopenia secondary to bone marrow failure. Laboratory work-up revealed severely shortened telomere length in both patients, and genetic testing revealed a missense mutation in the gene that encodes the reverse transcriptase component of telomerase, confirming the diagnosis of dyskeratosis congenita. The father of both children was a carrier of the same mutation, who exhibited marked retinal vascular tortuosity of the second-order vessels. Conclusion Dyskeratosis congenita is a severe multisystem disorder, which should be considered in cases of pediatric Exudative retinopathies with concurrent signs and/or symptoms of bone marrow failure.
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Familial Exudative Vitreoretinopathy
2015Co-Authors: Selçuk Sızmaz, Yoshihiro Yonekawa, Michael T. TreseAbstract:Familial Exudative Vitreoretinopathy (FEVR) is a hereditary disease associated with visual loss, particularly in the pediatric group. Mutations in the NDP, FZD4, LRP5, and TSPAN12 genes have been shown to contribute to FEVR. FEVR has been reported to have X-linked recessive, autosomal dominant, and autosomal recessive inheritances. However, both the genotypic and phenotypic features are variable. Novel mutations contributing to the disease have been reported. The earliest and the most prominent finding of the disease is avascularity in the peripheral retina. As the disease progresses, retinal neovascularization, subretinal exudation, partial and total retinal detachment may occur, which may be associated with certain mutations. With early diagnosis and prompt management visual loss can be prevented with laser photocoagulation and anti-VEGF injections. In case of retinal detachment, pars plana vitrectomy alone or combined with scleral buckling should be considered. Identifying asymptomatic family members with various degrees of insidious findings is of certain importance. Wide-field imaging with fluorescein angiography is crucial in the management of this disease. The differential diagnosis includes other pediatric vitreoretinopathies such as Norrie disease, retinopathy of prematurity, and Coats’ disease. (Turk J Ophthalmol 2015; 45: 164-168
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diversity of retinal vascular anomalies in patients with Familial Exudative Vitreoretinopathy
2014Co-Authors: Amir H Kashani, Kimberly A. Drenser, Antonio Capone, Kevin T Brown, Emmanuel Chang, Michael T. TreseAbstract:Purpose To describe the diversity of clinical findings associated with Familial Exudative Vitreoretinopathy (FEVR) using wide-field angiography and to update the current classification system. Design Retrospective case series at a single tertiary referral vitreoretinal practice. Participants A total of 174 eyes of 87 subjects were studied. Methods A retrospective chart review was conducted of patients with a diagnosis of FEVR between January 2011 and January 2013 at a single tertiary care retina practice. Data were collected from patient charts, including sex, gestational age at birth, age at presentation, referring diagnosis, family history, prior ocular surgery, clinical presentation, and diagnostic imaging in each eye. Inclusion criteria included clinical diagnosis of FEVR in patients referred to our clinic for evaluation of decreased vision. Patients were excluded if a diagnosis of FEVR could not be made. Main Outcome Measures Clinical and angiographic findings. Results A total of 87 subjects met the inclusion criteria for this study. A broad spectrum of previously undescribed clinical and angiographic findings were associated with FEVR on wide-field angiography. These findings can be grossly divided into anatomic and functional changes. Anatomic changes include aberrant circumferential peripheral vessels, venous and arterial tortuosity, late-phase disc leakage, central and peripheral telangiectasias, capillary anomalies, and capillary agenesis. Functional changes include venous-venous shunting, delayed arteriovenous transit, and delayed or absent choroidal perfusion on fluorescein angiography. Conclusions Familial Exudative Vitreoretinopathy has a wide range of unrecognized or under-recognized clinical and angiographic findings that are easily identified using wide-field fluorescein angiography. These novel findings have led to an update of the original FEVR classification scheme and more complete characterization of early stages of FEVR.
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clinical presentation of Familial Exudative Vitreoretinopathy
2011Co-Authors: Tushar M Ranchod, Antonio Capone, Kimberly A. Drenser, Michael T. TreseAbstract:Objective To describe the clinical characteristics, staging and presentation of patients with Familial Exudative Vitreoretinopathy (FEVR) in our clinical practice over the last 25 years. Design Case series, retrospective review. Participants We included 273 eyes of 145 patients. Methods Data collected from charts included gender, gestational age at birth, birthweight, age at presentation, referring diagnosis, family history, prior ocular surgery, and clinical presentation in each eye. Eyes with invasive posterior segment procedures before initial presentation were excluded. Main Outcome Measures Demographics on presentation and clinical staging. Results Patients were slightly male predominant (57%) with a mean birthweight of 2.80 kg (range, 740 g–4.76 kg), mean gestational age of 37.8 weeks (range, 25–42), and mean age at presentation of almost 6 years (range, Conclusions The FEVR patient population is remarkable for the wide range of age at presentation, gestational age, and birthweight. Although a positive family history on presentation may support the diagnosis of FEVR, a negative family history is of little help. The majority of retinal folds extended radially in the temporal quadrants, but radial folds were seen in almost all quadrants. Fellow eyes demonstrated a wide variation in symmetry. The presentation of FEVR may mimic the presentation of other pediatric and adult vitreoretinal disorders, and careful examination is often crucial in making the diagnosis of FEVR. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Ping Fei - One of the best experts on this subject based on the ideXlab platform.
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intravitreal ranibizumab treatment for advanced Familial Exudative Vitreoretinopathy with high vascular activity
2021Co-Authors: Jiao Lyu, Xiang Zhang, Qi Zhang, Ping Fei, Peiquan ZhaoAbstract:PURPOSE To determine the efficacy of intravitreal ranibizumab (IVR) treatment for advanced Familial Exudative Vitreoretinopathy with high vascular activity. METHODS The retrospective interventional case series included 28 eyes (20 patients) that had IVR in combination or not with other treatment, for Stage 3 to 5 Familial Exudative Vitreoretinopathy with active fibrovascular proliferation and prominent subretinal exudation. Outcome measures were fundus features after treatment, associated clinical variables, and genetic mutations. RESULTS The age of patients at the first IVR ranged from 0.2 to 36 months. An average of 1.3 IVR injections per eye were given. Familial Exudative Vitreoretinopathy regressed in 16 (57%) eyes and progressed in 12 eyes (43%) after IVR. Laser and/or vitrectomy was performed on 13 eyes. The retina was reattached in 22 eyes (78%) after 24 to 58 months follow-up. Clinical variables associated with progression after IVR were preexisting fibrovascular proliferation over one quadrant and persistent vascular activity after the initial injection (P < 0.05). Familial Exudative Vitreoretinopathy-causative genetic mutations in 11 patients were related to variable response to IVR treatment. CONCLUSION Intravitreal ranibizumab treatment may effectively regress advanced Familial Exudative Vitreoretinopathy with high vascular activity in selected cases. Different treatment outcomes may be relevant to variable presentation and genetic heterogeneity of Familial Exudative Vitreoretinopathy.
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catenin α 1 mutations cause Familial Exudative Vitreoretinopathy by overactivating norrin β catenin signaling
2021Co-Authors: Xianjun Zhu, Lulin Huang, Yeming Yang, Peiquan Zhao, Mu Yang, Shanshan Zhang, Lin Zhang, Ping Fei, Yi Huang, Ye YuanAbstract:Familial Exudative Vitreoretinopathy (FEVR) is a severe retinal vascular disease that causes blindness. FEVR has been linked to mutations in several genes associated with inactivation of the Norrin/β-catenin signaling pathway, but these account for only approximately 50% of cases. We report that mutations in CTNNA1 (α-catenin) cause FEVR by overactivating the β-catenin pathway and disrupting cell adherens junctions. Three heterozygous mutations in CTNNA1 (p.F72S, p.R376Cfs*27 and p.P893L) were identified by exome-sequencing. We further demon-strated that FEVR-associated mutations led to overactivation of Norrin/β-catenin signaling due to impaired protein interactions within the cadherin/catenin complex. The clinical features of FEVR were reproduced in mice lacking Ctnna1 in vascular endothelial cells (ECs) or with overactivat-ed β-catenin signaling by an EC-specific gain-of-function allele of Ctnnb1. In isolated mouse lung endothelial cells, both CTNNA1-P893L and F72S mutants failed to rescue either the dis-rupted F-ACTIN arrangement or VE-Cadherin and CTNNB1 distribution. Moreover, we discov-ered that compound heterozygous Ctnna1 F72S and a deletion allele could cause similar pheno-type. Furthermore, a LRP5 mutation, which activates Norrin/β-catenin signaling, was identified in a FEVR family and the corresponding knock-in mice exhibited partial FEVR-like phenotype. Our study demonstrates that precise regulation of β-catenin activation is critical for retinal vascu-lar development and provides new insights into the pathogenesis of FEVR.
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catenin alpha 1 mutations cause Familial Exudative Vitreoretinopathy by overactivating norrin beta catenin signaling
2021Co-Authors: Xianjun Zhu, Lulin Huang, Yeming Yang, Peiquan Zhao, Mu Yang, Shanshan Zhang, Lin Zhang, Ping Fei, Yi Huang, Ye YuanAbstract:Familial Exudative Vitreoretinopathy (FEVR) is a severe retinal vascular disease that causes blindness. FEVR has been linked to mutations in several genes associated with inactivation of the Norrin/β-catenin signaling pathway, but these account for only approximately 50% of cases. We report that mutations in CTNNA1 (α-catenin) cause FEVR by overactivating the β-catenin pathway and disrupting cell adherens junctions. Three heterozygous mutations in CTNNA1 (p.F72S, p.R376Cfs*27 and p.P893L) were identified by exome-sequencing. We further demon-strated that FEVR-associated mutations led to overactivation of Norrin/β-catenin signaling due to impaired protein interactions within the cadherin/catenin complex. The clinical features of FEVR were reproduced in mice lacking Ctnna1 in vascular endothelial cells (ECs) or with overactivat-ed β-catenin signaling by an EC-specific gain-of-function allele of Ctnnb1. In isolated mouse lung endothelial cells, both CTNNA1-P893L and F72S mutants failed to rescue either the dis-rupted F-ACTIN arrangement or VE-Cadherin and CTNNB1 distribution. Moreover, we discov-ered that compound heterozygous Ctnna1 F72S and a deletion allele could cause similar pheno-type. Furthermore, a LRP5 mutation, which activates Norrin/β-catenin signaling, was identified in a FEVR family and the corresponding knock-in mice exhibited partial FEVR-like phenotype. Our study demonstrates that precise regulation of β-catenin activation is critical for retinal vascu-lar development and provides new insights into the pathogenesis of FEVR.
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exome sequencing revealed notch ligand jag1 as a novel candidate gene for Familial Exudative Vitreoretinopathy
2020Co-Authors: Lin Zhang, Lulin Huang, Yeming Yang, Peiquan Zhao, Mu Yang, Shanshan Zhang, Xiang Zhang, Ping Fei, Wenjing Liu, Xianjun ZhuAbstract:Familial Exudative Vitreoretinopathy (FEVR) is a blindness-causing retinal vascular disease characterized by incomplete vascularization of the peripheral retina and by the absence or abnormality of the second/tertiary capillary layers in the deep retina. Variants in known FEVR disease genes can only explain about 50% of FEVR-affected cases. We aim to identify additional disease genes in patients with FEVR. We applied exome sequencing analysis in a cohort of 49 FEVR families without pathogenic variants in known FEVR genes. Functions of the affected proteins were evaluated by reporter assay. Knockout mouse models were generated by endothelial-specific Cre line. Three novel rare heterozygous variants in Notch ligand JAG1 were identified in FEVR families—c.413C>T p. (A138V), c.1415G>A p. (R472H), and c.2884A>G p. (T962A)—and verified by Sanger sequencing analysis. Notch reporter assay revealed that mutant JAG1 proteins JAG1-A138V and JAG1-T962A lost almost all of their activities, and JAG1-R472H lost approximately 50% of its activity. Deletion of Jag1 in mouse endothelial cells resulted in reduced tip cells at the angiogenic front and retarded vessel growth, reproducing FEVR-like phenotypes. Our data suggest that JAG1 is a novel candidate gene for FEVR and pinpoints a potential target for therapeutic intervention.
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the characteristics of digenic Familial Exudative Vitreoretinopathy
2018Co-Authors: Jie Peng, Qi Zhang, Xiang Zhang, Ping Fei, Kaiqin She, Peiquan ZhaoAbstract:To describe and analyse the clinical and genetic characteristics of digenic Familial Exudative Vitreoretinopathy (FEVR). The study cohort consisted of patients with FEVR (n = 13) to identify patients with two mutations in two different genes. A genetic analysis of the LRP5, FZD4, TSPAN12, and ZNF408 genes was performed with next-generation sequencing (NGS). The genotype data obtained from the patients with FEVR were analysed and correlated with their clinical manifestations. They were then further evaluated in conjunction with other data that were available for these genes. The probands and parents/relatives underwent comprehensive age-appropriate ophthalmic examinations. The medical history and genetic reports of 487 patients with FEVR were reviewed. In all, we identified 13 probands (2.67%, 13/487) with simultaneous mutations in two disease-causing genes. A total of 25 of mutations were found, including10 in FZD4, 8 in LRP5, 3 in ZNF408, 2 in NDP, and 2 in TSPAN12. The most frequent mutations were those in FZD4 and LRP5. We identified 8 mutations that had previously been identified and 17 novel variants. Among 26 eyes, 65.38% exhibited a phenotype, and 10 (38.46%) were stage 4, while 7 (26.92%) were stage 5. This is the first study to report a group of patients with digenic FEVR. In most affected eyes, the stage was more severe than stage 3. We speculate that the phenotype of FEVR is more severe in patients with digenic rather than monogenic variants of FEVR-related genes.
Xiang Zhang - One of the best experts on this subject based on the ideXlab platform.
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intravitreal ranibizumab treatment for advanced Familial Exudative Vitreoretinopathy with high vascular activity
2021Co-Authors: Jiao Lyu, Xiang Zhang, Qi Zhang, Ping Fei, Peiquan ZhaoAbstract:PURPOSE To determine the efficacy of intravitreal ranibizumab (IVR) treatment for advanced Familial Exudative Vitreoretinopathy with high vascular activity. METHODS The retrospective interventional case series included 28 eyes (20 patients) that had IVR in combination or not with other treatment, for Stage 3 to 5 Familial Exudative Vitreoretinopathy with active fibrovascular proliferation and prominent subretinal exudation. Outcome measures were fundus features after treatment, associated clinical variables, and genetic mutations. RESULTS The age of patients at the first IVR ranged from 0.2 to 36 months. An average of 1.3 IVR injections per eye were given. Familial Exudative Vitreoretinopathy regressed in 16 (57%) eyes and progressed in 12 eyes (43%) after IVR. Laser and/or vitrectomy was performed on 13 eyes. The retina was reattached in 22 eyes (78%) after 24 to 58 months follow-up. Clinical variables associated with progression after IVR were preexisting fibrovascular proliferation over one quadrant and persistent vascular activity after the initial injection (P < 0.05). Familial Exudative Vitreoretinopathy-causative genetic mutations in 11 patients were related to variable response to IVR treatment. CONCLUSION Intravitreal ranibizumab treatment may effectively regress advanced Familial Exudative Vitreoretinopathy with high vascular activity in selected cases. Different treatment outcomes may be relevant to variable presentation and genetic heterogeneity of Familial Exudative Vitreoretinopathy.
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whole exome sequencing identified dlg1 as a candidate gene for Familial Exudative Vitreoretinopathy
2021Co-Authors: Lulin Huang, Mu Yang, Shanshan Zhang, Xiang Zhang, Wenjing LiuAbstract:Purpose: Familial Exudative Vitreoretinopathy (FEVR) is a blinding retinal vascular disease. Clinically, FEVR is characterized by incomplete vascularization of the peripheral retina and pathological neovascularization. Only about 50% of FEVR cases can be explained by known FEVR disease gene variations. This study aimed to identify novel genes associated with the FEVR phenotype and explore their pathogenic mechanisms. Materials and Methods: Exome sequencing analyses were conducted on one Chinese family with FEVR whose affected members did not exhibit pathogenic variants in the known FEVR genes (verified using Sanger sequencing analysis). Functions of the affected proteins were evaluated using reporter assays. Western blot analysis was used to detect mutant protein expression and the genes' pathogenic mechanisms. Results: A rare novel heterozygous variant in DLG1 (c.1792A>G; p.S598G) was identified. The amino acid residues surrounding the identified variant are highly conserved among vertebrates. A luciferase reporter assay revealed that the mutant DLG1 protein DLG1-S598G lost its ability to activate Wnt signaling. Moreover, a knockdown (KD) of DLG1 in human primary retinal endothelial cells impaired tube formation. Mechanistically, DLG1 KD led to a reduction in phosphorylated VEGFR2, an essential receptor for the angiogenic potency that signals the vascular endothelial growth factor molecule. Conclusions: The data reported here demonstrate that DLG1 is a novel candidate gene for FEVR.
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exome sequencing revealed notch ligand jag1 as a novel candidate gene for Familial Exudative Vitreoretinopathy
2020Co-Authors: Lin Zhang, Shujin Li, Lulin Huang, Yeming Yang, Peiquan Zhao, Huijuan Xu, Mu Yang, Shanshan Zhang, Xiang Zhang, Zhenglin YangAbstract:PURPOSE: Familial Exudative Vitreoretinopathy (FEVR) is a blindness-causing retinal vascular disease characterized by incomplete vascularization of the peripheral retina and by the absence or abnormality of the second/tertiary capillary layers in the deep retina. Variants in known FEVR disease genes can only explain about 50% of FEVR-affected cases. We aim to identify additional disease genes in patients with FEVR. METHODS: We applied exome sequencing analysis in a cohort of 49 FEVR families without pathogenic variants in known FEVR genes. Functions of the affected proteins were evaluated by reporter assay. Knockout mouse models were generated by endothelial-specific Cre line. RESULTS: Three novel rare heterozygous variants in Notch ligand JAG1 were identified in FEVR families-c.413C>T p. (A138V), c.1415G>A p. (R472H), and c.2884A>G p. (T962A)-and verified by Sanger sequencing analysis. Notch reporter assay revealed that mutant JAG1 proteins JAG1-A138V and JAG1-T962A lost almost all of their activities, and JAG1-R472H lost approximately 50% of its activity. Deletion of Jag1 in mouse endothelial cells resulted in reduced tip cells at the angiogenic front and retarded vessel growth, reproducing FEVR-like phenotypes. CONCLUSION: Our data suggest that JAG1 is a novel candidate gene for FEVR and pinpoints a potential target for therapeutic intervention.
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exome sequencing revealed notch ligand jag1 as a novel candidate gene for Familial Exudative Vitreoretinopathy
2020Co-Authors: Lin Zhang, Lulin Huang, Yeming Yang, Peiquan Zhao, Mu Yang, Shanshan Zhang, Xiang Zhang, Ping Fei, Wenjing Liu, Xianjun ZhuAbstract:Familial Exudative Vitreoretinopathy (FEVR) is a blindness-causing retinal vascular disease characterized by incomplete vascularization of the peripheral retina and by the absence or abnormality of the second/tertiary capillary layers in the deep retina. Variants in known FEVR disease genes can only explain about 50% of FEVR-affected cases. We aim to identify additional disease genes in patients with FEVR. We applied exome sequencing analysis in a cohort of 49 FEVR families without pathogenic variants in known FEVR genes. Functions of the affected proteins were evaluated by reporter assay. Knockout mouse models were generated by endothelial-specific Cre line. Three novel rare heterozygous variants in Notch ligand JAG1 were identified in FEVR families—c.413C>T p. (A138V), c.1415G>A p. (R472H), and c.2884A>G p. (T962A)—and verified by Sanger sequencing analysis. Notch reporter assay revealed that mutant JAG1 proteins JAG1-A138V and JAG1-T962A lost almost all of their activities, and JAG1-R472H lost approximately 50% of its activity. Deletion of Jag1 in mouse endothelial cells resulted in reduced tip cells at the angiogenic front and retarded vessel growth, reproducing FEVR-like phenotypes. Our data suggest that JAG1 is a novel candidate gene for FEVR and pinpoints a potential target for therapeutic intervention.
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prenatal diagnosis of Familial Exudative Vitreoretinopathy and norrie disease
2019Co-Authors: Jingjing Liu, Qi Zhang, Xiang Zhang, Jing Zhu, J Yang, Peiquan ZhaoAbstract:BACKGROUND Both Familial Exudative Vitreoretinopathy (FEVR) and Norrie disease (ND) are hereditary retinal disorders which can cause severe visual impairment and blindness at a young age. The present study aimed to report the use of antenatal genetic testing and ultrasound in the diagnosis and counseling of FEVR and ND. METHODS Amniocentesis and ultrasonography were performed in high-risk mothers, with children having FEVR or ND, to predict severe ocular abnormalities. RESULTS Case 1: A homozygous NDP mutation (c.376T>C, NM_000266) was detected in the proband and his mother. Molecular prenatal analysis of the fetal DNA revealed no mutations. No ocular abnormalities were detected on ultrasonography. The pregnancy progressed uneventfully to a normal outcome. Case 2: A novel heterozygous FZD4 mutation (c.1010dupA, NM_012193) was detected in the proband and his mother. The same mutation was detected in the fetus, but ultrasonography showed no ocular abnormalities. A healthy baby boy with stage 1 FEVR was born after an uneventful pregnancy. Case 3: Deletions of exons 2 and 3 in the NDP were found in the proband and his mother. The same deletion mutation was detected in the female fetus, but the ultrasound scan was normal. The pregnancy progressed uneventfully to a normal outcome. CONCLUSIONS To our knowledge, antenatal genetic analyses were used in conjunction with ultrasound for the first time, to diagnose FEVR and ND, and predict the postnatal prognoses in at-risk babies.
Zhenglin Yang - One of the best experts on this subject based on the ideXlab platform.
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exome sequencing revealed notch ligand jag1 as a novel candidate gene for Familial Exudative Vitreoretinopathy
2020Co-Authors: Lin Zhang, Shujin Li, Lulin Huang, Yeming Yang, Peiquan Zhao, Huijuan Xu, Mu Yang, Shanshan Zhang, Xiang Zhang, Zhenglin YangAbstract:PURPOSE: Familial Exudative Vitreoretinopathy (FEVR) is a blindness-causing retinal vascular disease characterized by incomplete vascularization of the peripheral retina and by the absence or abnormality of the second/tertiary capillary layers in the deep retina. Variants in known FEVR disease genes can only explain about 50% of FEVR-affected cases. We aim to identify additional disease genes in patients with FEVR. METHODS: We applied exome sequencing analysis in a cohort of 49 FEVR families without pathogenic variants in known FEVR genes. Functions of the affected proteins were evaluated by reporter assay. Knockout mouse models were generated by endothelial-specific Cre line. RESULTS: Three novel rare heterozygous variants in Notch ligand JAG1 were identified in FEVR families-c.413C>T p. (A138V), c.1415G>A p. (R472H), and c.2884A>G p. (T962A)-and verified by Sanger sequencing analysis. Notch reporter assay revealed that mutant JAG1 proteins JAG1-A138V and JAG1-T962A lost almost all of their activities, and JAG1-R472H lost approximately 50% of its activity. Deletion of Jag1 in mouse endothelial cells resulted in reduced tip cells at the angiogenic front and retarded vessel growth, reproducing FEVR-like phenotypes. CONCLUSION: Our data suggest that JAG1 is a novel candidate gene for FEVR and pinpoints a potential target for therapeutic intervention.
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identification of two novel lrp5 mutations in families with Familial Exudative Vitreoretinopathy
2014Co-Authors: Ping Fei, Peiquan Zhao, Qi Zhang, Luling Huang, Xiong Zhu, Zhengfu Tai, Bo Gong, Quanyao Yao, Zhenglin YangAbstract:Purpose To investigate the clinical features and disease-causing mutations in two Chinese families with Familial Exudative Vitreoretinopathy (FEVR).
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mutations in lrp5 or fzd4 underlie the common Familial Exudative Vitreoretinopathy locus on chromosome 11q
2004Co-Authors: Carmel Toomes, H M Bottomley, Zhenglin Yang, David A Mackey, Richard M Jackson, Katherine V Towns, Sheila Scott, Jamie E Craig, Li Jiang, Richard C. TrembathAbstract:Familial Exudative Vitreoretinopathy (FEVR) is an inherited blinding disorder of the retinal vascular system. Autosomal dominant FEVR is genetically heterogeneous, but its principal locus, EVR1, is on chromosome 11q13-q23. The gene encoding the Wnt receptor frizzled-4 (FZD4) was recently reported to be the EVR1 gene, but our mutation screen revealed fewer patients harboring mutations than expected. Here, we describe mutations in a second gene at the EVR1 locus, low-density-lipoprotein receptor–related protein 5 (LRP5), a Wnt coreceptor. This finding further underlines the significance of Wnt signaling in the vascularization of the eye and highlights the potential dangers of using multiple families to refine genetic intervals in gene-identification studies.