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Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated <jats:italic>GEN1<\/jats:italic> as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between <jats:italic>GEN1<\/jats:italic> and human CAKUT.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>In this study, DNA from 910 individuals with CAKUT was collected; 26 <jats:italic>GEN1<\/jats:italic> rare variants were identified, and two <jats:italic>GEN1<\/jats:italic> (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071\u2009+\u20093(IVS10) A\u2009&gt;\u2009G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the <jats:italic>Gen1<\/jats:italic> variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071\u2009+\u20093(IVS10) A\u2009&gt;\u2009G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068\u2009+\u20093\u00a0A\u2009&gt;\u2009G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Overall, our findings indicated <jats:italic>GEN1<\/jats:italic> as a risk factor for human CAKUT.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40246-024-00606-8","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T02:01:51Z","timestamp":1713924111000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract"],"prefix":"10.1186","volume":"18","author":[{"given":"Xuanjin","family":"Du","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jialu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minghui","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haixin","family":"Ju","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanshan","family":"Xue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaxin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaojiao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rufeng","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihui","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Rao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yubo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohui","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3056-6737","authenticated-orcid":false,"given":"Qian","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,4,24]]},"reference":[{"issue":"9722","key":"606_CR1","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1016\/S0140-6736(10)60236-X","volume":"375","author":"F Hildebrandt","year":"2010","unstructured":"Hildebrandt F. 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The study was conducted in accordance with the ethical standards of the Committee on Human Experimentation. The animals were maintained and managed according to the animal welfare and usage management regulations of the School of Life Sciences of Fudan University [Protocol Approval No. SYXK (hu) 2020\u20130032]. Informed consent was obtained from all guardians. Animal experiments were approved by the Institutional Review Board of Fudan University.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}],"article-number":"41"}}