PMID- 33945310 OWN - NLM STAT- MEDLINE DCOM- 20211207 LR - 20221207 IS - 1945-0257 (Electronic) IS - 1945-0257 (Linking) VI - 25 IP - 5 DP - 2021 May TI - Whole-Exome Sequencing Identified DLG1 as a Candidate Gene for Familial Exudative Vitreoretinopathy. PG - 309-316 LID - 10.1089/gtmb.2021.0013 [doi] AB - 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. FAU - Zhang, Shanshan AU - Zhang S AUID- ORCID: 0000-0002-2430-1807 AD - The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. AD - Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. FAU - Li, Xiao AU - Li X AD - The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. AD - Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. FAU - Liu, Wenjing AU - Liu W AD - The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. AD - Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. FAU - Zhang, Xiang AU - Zhang X AD - Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Huang, Lulin AU - Huang L AD - The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. AD - Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. FAU - Li, Shujin AU - Li S AD - The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. AD - Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. AD - Chengdu Institute of Biology, Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China. FAU - Yang, Mu AU - Yang M AUID- ORCID: 0000-0002-6001-6827 AD - The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. AD - Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. AD - Chengdu Institute of Biology, Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China. FAU - Zhao, Peiquan AU - Zhao P AD - Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Yang, Jiyun AU - Yang J AUID- ORCID: 0000-0002-1064-4681 AD - The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. AD - Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. FAU - Fei, Ping AU - Fei P AD - Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Zhu, Xianjun AU - Zhu X AUID- ORCID: 0000-0002-2531-7552 AD - The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. AD - Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. AD - Chengdu Institute of Biology, Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China. FAU - Yang, Zhenglin AU - Yang Z AD - The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. AD - Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. AD - Chengdu Institute of Biology, Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China. LA - eng PT - Case Reports PT - Journal Article DEP - 20210504 PL - United States TA - Genet Test Mol Biomarkers JT - Genetic testing and molecular biomarkers JID - 101494210 RN - 0 (DLG1 protein, human) RN - 0 (Discs Large Homolog 1 Protein) SB - IM MH - Adult MH - Asian People/genetics MH - Child MH - China MH - DNA Mutational Analysis MH - Discs Large Homolog 1 Protein/*genetics/metabolism MH - Endothelial Cells MH - Eye Diseases, Hereditary MH - Familial Exudative Vitreoretinopathies/*genetics MH - Female MH - Humans MH - Male MH - Mutation MH - Mutation, Missense MH - Pedigree MH - Phenotype MH - Retinal Diseases/genetics MH - Exome Sequencing/methods OTO - NOTNLM OT - DLG1 OT - FEVR OT - angiogenesis OT - mutations OT - whole-exome sequencing EDAT- 2021/05/05 06:00 MHDA- 2021/12/15 06:00 CRDT- 2021/05/04 17:14 PHST- 2021/05/05 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/05/04 17:14 [entrez] AID - 10.1089/gtmb.2021.0013 [doi] PST - ppublish SO - Genet Test Mol Biomarkers. 2021 May;25(5):309-316. doi: 10.1089/gtmb.2021.0013. Epub 2021 May 4.