{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:11:56Z","timestamp":1753891916077,"version":"3.41.2"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T00:00:00Z","timestamp":1746662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Alport syndrome is an inherited glomerular disease that leads to progressive kidney failure, hearing loss, and eye problems. Diagnosis mostly relies on tests of tissue pathology and genetic analysis. This study aims to clarify the role of the <jats:italic>COL4A4<\/jats:italic> c.817-1G\u2009&amp;gt;\u2009A mutation in Alport syndrome. The <jats:italic>COL4A4<\/jats:italic> gene encodes the \u03b14 chain of type IV collagen, which is a key component of the glomerular basement membrane. Mutations in this gene are strongly linked to Alport syndrome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We collected clinical data from a 12-year-old boy who had \u201cpersistent hematuria for 4 years\u201d and performed a renal biopsy, which was pathologically diagnosed as \u201cAlport syndrome\u201d. We used high-throughput sequencing technology to conduct whole-exome sequencing (WES) and Sanger sequencing for the patient and his parents. Through bioinformatics analysis, we found that the <jats:italic>COL4A4<\/jats:italic> c.817-1G\u2009&amp;gt;\u2009A mutation may lead to splicing abnormalities. We extracted RNA from the patients blood and urine samples and used <jats:italic>in vivo<\/jats:italic> splicing validation to study the impact of the mutation on mRNA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our findings show that the COL4A4 c.817-1G\u2009&amp;gt;\u2009A mutation disrupts mRNA splicing. This mutation affects the splice acceptor site of Intron 13, which is next to Exon 14, causing a 1-bp deletion before Exon 14 and creating a premature stop codon. Consequently, a truncated protein of 273 amino acids is produced, as opposed to the full-length protein of 1,690 amino acids. This finding clarifies the molecular mechanism by which this mutation contributes to Alport syndrome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study finds that the <jats:italic>COL4A4<\/jats:italic> c.817-1G\u2009&amp;gt;\u2009A variant may cause autosomal dominant Alport syndrome. Our research expands the mutation spectrum of Alport syndrome while aiding in genetic counseling and diagnosis for affected patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2025.1533638","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T04:13:05Z","timestamp":1746677585000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The heterozygous mutation COL4A4 c.817-1G&gt;A causes Alport syndrome in a Chinese family: a case report"],"prefix":"10.3389","volume":"13","author":[{"given":"Dayan","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaichao","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lanjin","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panjian","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1053\/j.ajkd.2020.03.026","article-title":"Alport syndrome: achieving early diagnosis and treatment","volume":"77","author":"Kashtan","year":"2021","journal-title":"Am J Kidney Dis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2740","DOI":"10.1681\/ASN.2013080912","article-title":"Improving mutation screening in familial hematuric nephropathies through next generation sequencing","volume":"25","author":"Moriniere","year":"2014","journal-title":"J Am Soc Nephrol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1093\/ndt\/gfy050","article-title":"Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children","volume":"34","author":"Schapiro","year":"2019","journal-title":"Nephrol Dial Transplant"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.1681\/ASN.2020071065","article-title":"Prevalence estimates of predicted pathogenic COL4A3-COL4A5 variants in a population sequencing database and their implications for Alport syndrome","volume":"32","author":"Gibson","year":"2021","journal-title":"J Am Soc Nephrol"},{"key":"B5","first-page":"1241","article-title":"X-linked inheritance of Alport syndrome: family P revisited","volume":"35","author":"Hasstedt","year":"1983","journal-title":"Am J Hum Genet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e00741","DOI":"10.1002\/mgg3.741","article-title":"Genotype-phenotype correlation and prognostic impact in Chinese patients with Alport syndrome","volume":"7","author":"Shang","year":"2019","journal-title":"Mol Genet Genomic Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.1093\/ndt\/12.8.1595","article-title":"Autosomal dominant Alport syndrome linked to the type IV collage alpha 3 and alpha 4 genes (COL4A3 and COL4A4)","volume":"12","author":"Jefferson","year":"1997","journal-title":"Nephrol Dial Transplant"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1111\/j.1523-1755.2004.00560.x","article-title":"Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene","volume":"65","author":"Pescucci","year":"2004","journal-title":"Kidney Int"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.2215\/CJN.01000116","article-title":"Genetic, clinical, and pathologic backgrounds of patients with autosomal dominant Alport syndrome","volume":"11","author":"Kamiyoshi","year":"2016","journal-title":"Clin J Am Soc Nephrol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1053\/j.ajkd.2021.02.326","article-title":"Clinical and genetic features of autosomal dominant Alport syndrome: a cohort study","volume":"78","author":"Furlano","year":"2021","journal-title":"Am J Kidney Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1093\/ndt\/gfn681","article-title":"Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome","volume":"24","author":"Marcocci","year":"2009","journal-title":"Nephrol Dial Transplant"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e883","DOI":"10.1002\/mgg3.883","article-title":"Comparison between conventional and comprehensive sequencing approaches for genetic diagnosis of Alport syndrome","volume":"7","author":"Yamamura","year":"2019","journal-title":"Mol Genet Genomic Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"841391","DOI":"10.3389\/fmed.2022.841391","article-title":"The contribution of COL4A5 splicing variants to the pathogenesis of X-linked Alport syndrome","volume":"9","author":"Yamamura","year":"2022","journal-title":"Front Med (Lausanne)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"838983","DOI":"10.3389\/fmed.2022.838983","article-title":"Presumed COL4A3\/COL4A4 missense\/synonymous variants induce aberrant splicing","volume":"9","author":"Deng","year":"2022","journal-title":"Front Med (Lausanne)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"22225","DOI":"10.1038\/s41598-021-01604-9","article-title":"Author correction: mRNA analysis identifies deep intronic variants causing Alport syndrome and overcomes the problem of negative results of exome sequencing","volume":"11","author":"Wang","year":"2021","journal-title":"Sci Rep"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1016\/j.ekir.2023.04.001","article-title":"Abnormal mRNA splicing effect of COL4A3 to COL4A5 unclassified variants","volume":"8","author":"Zhang","year":"2023","journal-title":"Kidney Int Rep"},{"key":"B17","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1053\/j.ajkd.2021.04.017","article-title":"Pathogenic variants in the genes affected in Alport syndrome (COL4A3-COL4A5) and their association with other kidney conditions: a review","volume":"78","author":"Savige","year":"2021","journal-title":"Am J Kidney Dis"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2025.1533638\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T04:13:06Z","timestamp":1746677586000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2025.1533638\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,8]]},"references-count":17,"alternative-id":["10.3389\/fped.2025.1533638"],"URL":"https:\/\/doi.org\/10.3389\/fped.2025.1533638","relation":{},"ISSN":["2296-2360"],"issn-type":[{"type":"electronic","value":"2296-2360"}],"subject":[],"published":{"date-parts":[[2025,5,8]]},"article-number":"1533638"}}