Mutation Spectrum of the LRP5, NDP, and TSPAN12 Genes in Chinese Patients With Familial Exudative Vitreoretinopathy

Tang, Miao; Sun, Limei; Hu, Andina; Yuan, Miner; Yu, Yang; Peng, Xuening; Ding, Xiaoyan

doi:10.1167/iovs.17-22577

Cited by 39 publications

(40 citation statements)

References 28 publications

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“…We cloned and characterized the human FZD4 gene in 1999 (92), and since then germline mutations in the FZD4 gene (such as C45Y, Y58C, W226X and W496X) have been reported in patients with exudative vitreoretinopathy (93–95) (Fig. 2).…”

Section: Vascular Diseasesmentioning

confidence: 99%

Molecular genetics and targeted therapy of WNT-related human diseases (Review)

Katoh¹,

2017

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Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and prostate cancers activate the WNT/β-catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other cancers activate the WNT/β-catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in B-cell leukemia and solid tumors and ROR2 upregulation in melanoma induce invasion, metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1, tankyrase and β-catenin are targets of anti-WNT signaling therapy, and ETC-159, LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab), PRI-724 and UC-961 (cirmtuzumab) are in clinical trials for cancer patients. Different classes of anti-WNT signaling therapeutics are necessary for the treatment of APC/CTNNB1-, RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human cancers. By contrast, Dickkopf-related protein 1 (DKK1), SOST and glycogen synthase kinase 3β (GSK3β) are targets of pro-WNT signaling therapy, and anti-DKK1 (BHQ880 and DKN-01) and anti-SOST (blosozumab, BPS804 and romosozumab) monoclonal antibodies are being tested in clinical trials for cancer patients and osteoporotic post-menopausal women. WNT-targeting therapeutics have also been applied as reagents for in vitro stem-cell processing in the field of regenerative medicine.

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Section: Vascular Diseasesmentioning

confidence: 99%

Molecular genetics and targeted therapy of WNT-related human diseases (Review)

Katoh¹,

2017

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“…Genetic testing for IRDs has led to a considerable increase in the number of new genes or identified mutations and has now become a major tool in daily clinical practice. In the past decades, in addition to the four classical genes, namely LRP5 (low‐density lipoprotein receptor‐related protein 5, OMIM *603506), FZD4 (frizzled, drosophila, homolog of, 4, OMIM *604579), NDP (NDP gene, OMIM *300658), and TSPAN12 (tetraspanin 12, OMIM *613138) in the Wnt signaling pathway, the genes KIF11 (kinesin family member 11, OMIM *148760), ZNF408 (zinc finger protein 408), and CTNNB1 (catenin, beta‐1, OMIM *116806) have recently been identified to be associated with FEVR (Hull et al, ; Poulter et al, ; Salvo et al, ; Tang et al, ). Genetic testing also facilitates the development of gene therapy for those once considered being untreatable IRDs (Jacobson et al, ; Sundaram et al, ), and human RPE 65 (ribulose 5‐phosphate 3‐epimerase 65, OMIM *180480) gene therapy for Leber's congenital amaurosis has been approved by the United States Food and Drug Administration (Pierce & Bennett, ).…”

Section: Introductionmentioning

confidence: 99%

Parents' perceptions of diagnostic genetic testing for children with inherited retinal disease in China

Wang

Huang

et al. 2019

Molec Gen & Gen Med

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Background In this study, we aim to investigate the awareness of, attitudes toward, and experiences with diagnostic genetic testing among parents of children suspected of having inherited retinal disease (IRDs) in China. Methods Semistructured, face‐to‐face, and in‐depth interviews were carried out with parents of children with suspected IRDs in this qualitative study. Inductive content analysis was used for data processing. Results Forty‐six parents participated in our interviews, and 47.8% of them supported genetic testing for following four main reasons: to help in making informed reproductive health decisions, to prepare for novel potential treatment, to identify the underlying causes of IRDs, and to satisfy curiosity about the heredity of IRDs. Among them, 19.6% were opposed to the testing for four main reasons, namely lack of therapeutic benefit, difficulty in affording the testing cost, doubt in the accuracy of clinical diagnosis, and the presence of concerns about the limitations of genetic testing. 47.8% of the parents expressed concerns that the genetic findings might lead to potential psychological stress. Conclusion In this study, we showed that nearly half of the parents supported genetic testing mainly for family planning, and a fifth of the parents were opposed to the testing mainly for lack of therapeutic benefit. Moreover, half of the parents expressed concern that a positive genetic result may create potential psychological burden to the parents and children.

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“…Our prior study showed that the first four genes associated with the Wnt pathway accounted for about 44% of classical FEVR probands with a broad spectrum of phenotypes. 9,19 Similarly, Salvo et al 13 and Rao et al 20 reported that mutations in the six genes account for 48.9% and 38.7% of FEVR patients, respectively. Furthermore, the reported mutation frequencies in the LRP5, TSPAN12, and FZD4 genes varied a lot across different populations.…”

Section: Discussionmentioning

confidence: 99%

“…Targeted next-generation sequencing was performed using a custom genetic pediatric retinal disease panel. 9 Identified mutation was validated by Sanger sequencing through family members. All coding sequences and intron-exon junctions were amplified and sequenced comprehensively, followed by cosegregation testing to verify suspected variants in the family members.…”

Section: Methodsmentioning

confidence: 99%

Next-Generation Sequencing in the Familial Exudative Vitreoretinopathy-Associated Rhegmatogenous Retinal Detachment

Chen

Wang

Sun

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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The purpose of this study was to investigate the genetic mutation spectrum in Chinese patients with familial exudative vitreoretinopathy-associated rhegmatogenous retinal detachment (FEVR-RRD) and to analyze the preliminary genotype-phenotype association. METHODS. In this consecutive, cross-sectional study, 54 patients with FEVR-RRD were studied. Comprehensive ophthalmic examinations and targeted next-generation sequencing were performed in all patients. The genotype-phenotype association was also analyzed. RESULTS. Causative mutations were identified in 38.9% (21/54) of patients (14/54 in LRP5, 4/ 54 in FDZ4, and 3/54 in TSPAN12). The study identified 22 potentially pathogenic mutations in 21 unrelated FEVR probands, and 14 were novel (10/15 in LRP5, 1/4 in FZD4, and 3/3 in TSPAN12). Furthermore, to explore the genotype-phenotype association, late-phase angiographic posterior and peripheral leakage (LAPPEL) was identified in 100% (4/4) of patients with FZD4 mutations and 100% (3/3) of patients with TSPAN12 mutations but only in 42.9% (6/14) of patients with LRP5 mutations. Extraretinal neovascularization (ERNV) was found in 100% (4/4) of patients with FZD4 mutations and in 66.7% (2/3) of patients with TSPAN12 mutations, but only in 21.4% (3/14) of patients with LRP5 mutations. CONCLUSIONS. The positive rate for pathogenic mutations in the known FEVR-associated genes was 38.9% (21/54). Among the mutations, LRP5 mutation was the predominant, accounting for 66.7% (14/21) of genetic positive patients. Patients with FEVR-RRD due to LRP5 mutations have less retinal vascular leakage or neovasculization than do patients with FEVR-RRD due to TSPAN12/FZD4 mutations. Moreover, 14 novel variants were found, which provided a deeper understanding of this disease.

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Mutation Spectrum of the LRP5, NDP, and TSPAN12 Genes in Chinese Patients With Familial Exudative Vitreoretinopathy

Cited by 39 publications

References 28 publications

Molecular genetics and targeted therapy of WNT-related human diseases (Review)

Molecular genetics and targeted therapy of WNT-related human diseases (Review)

Parents' perceptions of diagnostic genetic testing for children with inherited retinal disease in China

Next-Generation Sequencing in the Familial Exudative Vitreoretinopathy-Associated Rhegmatogenous Retinal Detachment

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