{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T04:46:19Z","timestamp":1776746779566,"version":"3.51.2"},"reference-count":25,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2024YFC2707002"],"award-info":[{"award-number":["2024YFC2707002"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2022YFC2705102"],"award-info":[{"award-number":["2022YFC2705102"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170683"],"award-info":[{"award-number":["82170683"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271890"],"award-info":[{"award-number":["82271890"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32570951"],"award-info":[{"award-number":["32570951"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Science and Technology Commission Natural Foundation Project","award":["23JC1401202"],"award-info":[{"award-number":["23JC1401202"]}]},{"name":"Shanghai Municipal Commission of Health","award":["20224Y0322"],"award-info":[{"award-number":["20224Y0322"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: X-linked Alport syndrome (XLAS) arises from pathogenic variants in COL4A5. Truncating variants are generally classified as severe, but whether clinically meaningful heterogeneity exists within this group remains unclear. This study aimed to establish a novel Col4a5 knock-in mouse model based on a clinical variant and to determine whether truncating mutation position influences disease severity. Methods: A de novo COL4A5 frameshift variant, c.2440delG, was identified in a patient with severe early-onset XLAS. A Col4a5-G814fs knock-in mouse was generated by CRISPR\/Cas9 on the C57BL\/6J inbred mouse strain background and compared with the established Col4a5-G5X nonsense model using survival analysis, serial functional measurements, kidney histopathology, transmission electron microscopy, and RNA sequencing. Results: The Col4a5-G814fs knock-in mouse was successfully generated and showed loss of glomerular \u03b15(IV) collagen chain expression. Compared with G5X mice, G814fs mice exhibited shorter survival (median 141 vs. 161.5 days, p = 0.0004), earlier onset of proteinuria, and more severe kidney functional decline. By 16 weeks, G814fs mice also showed more severe glomerular basement membrane abnormalities and more extensive glomerulosclerosis. RNA sequencing revealed a shared inflammatory gene signature in both models, together with selective upregulation of genes related to the PPAR signaling pathway and fatty acid metabolism in G814fs kidneys. Conclusions: This study reports a novel de novo COL4A5 frameshift variant and establishes the first Col4a5-G814fs knock-in mouse model. Direct comparison with the G5X model shows that distinct truncating COL4A5 mutations can be associated with substantially different disease severity, providing a useful platform for future mechanistic and therapeutic studies in XLAS.<\/jats:p>","DOI":"10.3390\/genes17040485","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T09:37:42Z","timestamp":1776677862000},"page":"485","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Col4a5-G814fs Knock-In Mouse Model Reveals Phenotypic Heterogeneity Among Truncating COL4A5 Mutations in X-Linked Alport Syndrome"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0895-5436","authenticated-orcid":false,"given":"Yingqi","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Nephrology, Rheumatology and Immunology, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3472-3744","authenticated-orcid":false,"given":"Lei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Rheumatology and Immunology, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Rheumatology and Immunology, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Kuang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Rheumatology and Immunology, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7203-2170","authenticated-orcid":false,"given":"Xiuli","family":"Gong","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China"},{"name":"NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0223-2517","authenticated-orcid":false,"given":"Qin","family":"Cai","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanwen","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Xu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2197-0781","authenticated-orcid":false,"given":"Wenyan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Rheumatology and Immunology, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China"},{"name":"NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7053-1614","authenticated-orcid":false,"given":"Fanyi","family":"Zeng","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Medical Genetics, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China"},{"name":"NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China"},{"name":"Department of Histo-Embryology, Genetics and Developmental Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","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. 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