{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T07:32:38Z","timestamp":1788593558776,"version":"build-2803163510"},"reference-count":26,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T00:00:00Z","timestamp":1592265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP19ek0109231h0003"],"award-info":[{"award-number":["JP19ek0109231h0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>X\u2010linked Alport syndrome (XLAS) is a progressive, hereditary glomerular nephritis of variable severity caused by pathogenic <jats:italic>COL4A5<\/jats:italic> variants. Currently, genetic testing is widely used for diagnosing XLAS; however, determining the pathogenicity of variants detected by such analyses can be difficult. Intronic variants or synonymous variants may cause inherited diseases by inducing aberrant splicing. Transcript analysis is necessary to confirm the pathogenicity of such variants, but it is sometimes difficult to extract mRNA directly from patient specimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we conducted in vitro splicing analysis using a hybrid minigene assay and specimens from three XLAS patients with synonymous variants causing aberrant splicing, including previously reported pathogenic mutations in the same codon. The variants were c.876 A&gt;T (p.Gly292=), c.2358 A&gt;G (p.Pro786=), and c.3906 A&gt;G (p.Gln1302=).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results from our hybrid minigene assay were sufficient to predict splicing abnormalities; c.876 A&gt;T cause 17\u2010bp del and 35\u2010bp del, c.2358 A&gt;G cause exon 29 skipping, c.3906 A&gt;G cause exon 42 skipping, which are very likely to cause pathogenicity. Further, patients carrying c.2358 A&gt;G exhibited a mild phenotype that may have been associated with the presence of both normal and abnormally spliced transcripts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The minigene system was shown to be a sensitive assay and a useful tool for investigating the pathogenicity of synonymous variants.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1342","type":"journal-article","created":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T11:44:01Z","timestamp":1592307841000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Pathogenic evaluation of synonymous <i>COL4A5<\/i> variants in X\u2010linked Alport syndrome using a minigene assay"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1655-6030","authenticated-orcid":false,"given":"Tomoko","family":"Horinouchi","sequence":"first","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Yamamura","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shogo","family":"Minamikawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"China","family":"Nagano","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Sakakibara","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Child Health and Welfare (Pediatrics) Graduate School of Medicine University of the Ryukyus Nishihara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Shima","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Wakayama Medical University Wakayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoya","family":"Morisada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Ishiko","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Aoto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Nagase","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rini","family":"Rossanti","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Ishimori","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kaito","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Matsuo","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy Faculty of Rehabilitation Kobe Gakuin University Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumoto","family":"Iijima","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0290-3137","authenticated-orcid":false,"given":"Kandai","family":"Nozu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kobe University Graduate School of Medicine Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22725"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096\u20108628(20010115)98:2<148:aid\u2010ajmg1024>3.0.co;2\u2010w"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2349482"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2009070784"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2018090909"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004670050025"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0178630"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006691"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5268"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157\u2010015\u20101197\u20109"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfv325"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.479"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V75702"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2018030228"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V114649"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1203\/pdr.0b013e318031935a"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V991736"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.12.018"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467\u2010016\u20103565\u20104"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581\u2010019\u20100229\u20101"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157\u2010018\u20101682\u2010z"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439\u2010009\u20100697\u20107"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157\u2010018\u20101629\u20104"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.2215\/cjn.04140414"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2019030218"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254806"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmgg3.1342","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1342","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.1342","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1342","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T11:17:29Z","timestamp":1708514249000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.1342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,16]]},"references-count":26,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,8]]}},"alternative-id":["10.1002\/mgg3.1342"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.1342","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,16]]},"assertion":[{"value":"2020-02-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-06-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e1342"}}