{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:32:26Z","timestamp":1789259546603,"version":"build-2803163510"},"reference-count":14,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070975"],"award-info":[{"award-number":["82070975"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770908"],"award-info":[{"award-number":["81770908"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070943"],"award-info":[{"award-number":["82070943"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018625","name":"Science and Technology Innovation Plan Of Shanghai Science and Technology Commission","doi-asserted-by":"publisher","award":["18411965200"],"award-info":[{"award-number":["18411965200"]}],"id":[{"id":"10.13039\/501100018625","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["21ZR1411400"],"award-info":[{"award-number":["21ZR1411400"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Hum Genomics"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>To report newly found <jats:italic>TSPAN12<\/jats:italic> mutations with a unique form of familial exudative vitreoretinopathy (FEVR) and find out the possible mechanism of a repeated novel intronic variant in <jats:italic>TSPAN12<\/jats:italic> led to FEVR.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Nine <jats:italic>TSPAN12<\/jats:italic> mutations with a unique form of FEVR were detected by panel-based NGS. MINI-Gene assay showed two splicing modes of mRNA that process two different bands A and B, and mutant-type shows replacement with the splicing mode of Exon11 hopping. Construction of wild-type and mutant <jats:italic>TSPAN12<\/jats:italic> vector showed the appearance of premature termination codons (PTC). In vitro expression detection showed significant down-regulated expression level of <jats:italic>TSPAN12<\/jats:italic> mRNAs and proteins in cells transfected with mutant vectors compared with in wild-type group. On the contrary, translation inhibitor CHX and small interfering RNA of UPF1 (si-UPF1) significantly increased mRNA or protein expression of <jats:italic>TSPAN12<\/jats:italic> in cells transfected with the mutant vectors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Nine mutations in <jats:italic>TSPAN12<\/jats:italic> gene are reported in 9 FEVR patients with a unique series of ocular abnormalities. The three novel <jats:italic>TSPAN12<\/jats:italic> mutations trigger NMD would cause the decrease of TSPAN12 proteins that participate in biosynthesis and assembly of microfibers, which might lead to FEVR, and suggest that intronic sequence analysis might be a vital tool for genetic counseling and prenatal diagnoses.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40246-024-00589-6","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T05:05:04Z","timestamp":1709269504000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Mutations in TSPAN12 gene causing familial exudative vitreoretinopathy"],"prefix":"10.1186","volume":"18","author":[{"given":"Yuqiao","family":"Ju","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,1]]},"reference":[{"issue":"4","key":"589_CR1","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1016\/0002-9394(69)91237-9","volume":"68","author":"VG Criswick","year":"1969","unstructured":"Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol. 1969;68(4):578\u201394.","journal-title":"Am J Ophthalmol"},{"issue":"24","key":"589_CR2","doi-asserted-by":"publisher","first-page":"9856","DOI":"10.1073\/pnas.1220864110","volume":"110","author":"RW Collin","year":"2013","unstructured":"Collin RW, Nikopoulos K, Dona M, et al. ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature. Proc Natl Acad Sci U S A. 2013;110(24):9856\u201361.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"589_CR3","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.ajhg.2009.12.016","volume":"86","author":"K Nikopoulos","year":"2010","unstructured":"Nikopoulos K, Gilissen C, Hoischen A, et al. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. Am J Hum Genet. 2010;86(2):240\u20137.","journal-title":"Am J Hum Genet"},{"issue":"2","key":"589_CR4","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/ng957","volume":"32","author":"J Robitaille","year":"2002","unstructured":"Robitaille J, MacDonald ML, Kaykas A, et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet. 2002;32(2):326\u201330.","journal-title":"Nat Genet"},{"issue":"2","key":"589_CR5","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.cell.2009.07.048","volume":"139","author":"HJ Junge","year":"2009","unstructured":"Junge HJ, Yang S, Burton JB, et al. TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4\/beta-catenin signaling. Cell. 2009;139(2):299\u2013311.","journal-title":"Cell"},{"issue":"3","key":"589_CR6","doi-asserted-by":"publisher","first-page":"587","DOI":"10.3390\/genes14030587","volume":"14","author":"Z Jiang","year":"2023","unstructured":"Jiang Z, Wang P. Novel exon 7 deletions in TSPAN12 in a three-generation FEVR family: a case report and literature review. Genes (Basel). 2023;14(3):587.","journal-title":"Genes (Basel)"},{"issue":"2","key":"589_CR7","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1136\/jmedgenet-2021-108259","volume":"60","author":"Y He","year":"2023","unstructured":"He Y, Yang M, Zhao R, et al. Novel truncating variants in CTNNB1 cause familial exudative vitreoretinopathy. J Med Genet. 2023;60(2):174\u201382.","journal-title":"J Med Genet"},{"issue":"4","key":"589_CR8","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1007\/s12098-023-04504-0","volume":"90","author":"H Sun","year":"2023","unstructured":"Sun H, Xia Z, Wang Z, et al. Mutations in the TSPAN12 and KIF11 genes in severe retinopathy of prematurity. Indian J Pediatr. 2023;90(4):408.","journal-title":"Indian J Pediatr"},{"issue":"1","key":"589_CR9","doi-asserted-by":"publisher","first-page":"3286","DOI":"10.1080\/07853890.2022.2146744","volume":"54","author":"J Mao","year":"2022","unstructured":"Mao J, Chen Y, Fang Y, et al. Clinical characteristics and mutation spectrum in 33 Chinese families with familial exudative vitreoretinopathy. Ann Med. 2022;54(1):3286\u201398.","journal-title":"Ann Med"},{"issue":"15","key":"589_CR10","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1167\/iovs.62.15.4","volume":"62","author":"T Tao","year":"2021","unstructured":"Tao T, Xu N, Li J, et al. Ocular features and mutation spectrum of patients with familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2021;62(15):4.","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"3","key":"589_CR11","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1111\/cge.14273","volume":"103","author":"R Zhao","year":"2023","unstructured":"Zhao R, Dai E, Wang S, et al. A comprehensive functional analysis on the pathogenesis of novel TSPAN12 and NDP variants in familial exudative vitreoretinopathy. Clin Genet. 2023;103(3):320\u20139.","journal-title":"Clin Genet"},{"issue":"6","key":"589_CR12","doi-asserted-by":"publisher","first-page":"e1949","DOI":"10.1002\/mgg3.1949","volume":"10","author":"L Peng","year":"2022","unstructured":"Peng L, Dai E, Xiao H, et al. A novel frameshift variant in the TSPAN12 gene causes autosomal dominant FEVR. Mol Genet Genomic Med. 2022;10(6):e1949.","journal-title":"Mol Genet Genomic Med"},{"issue":"3","key":"589_CR13","doi-asserted-by":"publisher","first-page":"495","DOI":"10.3390\/genes13030495","volume":"13","author":"AP Cicerone","year":"2022","unstructured":"Cicerone AP, Dailey W, Sun M, et al. A survey of multigenic protein-altering variant frequency in familial exudative vitreo-retinopathy (FEVR) patients by targeted sequencing of seven FEVR-linked genes. Genes (Basel). 2022;13(3):495.","journal-title":"Genes (Basel)"},{"issue":"50","key":"589_CR14","doi-asserted-by":"publisher","first-page":"E11827","DOI":"10.1073\/pnas.1813217115","volume":"115","author":"Y Wang","year":"2018","unstructured":"Wang Y, Cho C, Williams J, et al. Interplay of the Norrin and Wnt7a\/Wnt7b signaling systems in blood-brain barrier and blood-retina barrier development and maintenance. Proc Natl Acad Sci U S A. 2018;115(50):E11827\u201336.","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Human Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40246-024-00589-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40246-024-00589-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40246-024-00589-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T05:06:48Z","timestamp":1709269608000},"score":1,"resource":{"primary":{"URL":"https:\/\/humgenomics.biomedcentral.com\/articles\/10.1186\/s40246-024-00589-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,1]]},"references-count":14,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["589"],"URL":"https:\/\/doi.org\/10.1186\/s40246-024-00589-6","relation":{},"ISSN":["1479-7364"],"issn-type":[{"value":"1479-7364","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,1]]},"assertion":[{"value":"16 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experiments were conducted as per the Helsinki Declaration tenets. This study was conducted in accordance with the approval fron the Ethical Oversight Committee of Eye and ENT Hospital of Fudan University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22"}}