{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:22:13Z","timestamp":1761920533631,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,12,5]],"date-time":"2018-12-05T00:00:00Z","timestamp":1543968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["RE 1723\/1-3"],"award-info":[{"award-number":["RE 1723\/1-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Genetic factors play a critical role in the development of human diseases. Recently, several molecular genetic studies have provided multiple lines of evidence for a critical role of genetic factors in the expression of human bladder exstrophy-epispadias complex (BEEC). At this point, ISL1 (ISL LIM homeobox 1) has emerged as the major susceptibility gene for classic bladder exstrophy (CBE), in a multifactorial disease model. Here, GWAS (Genome wide association studies) discovery and replication studies, as well as the re-sequencing of ISL1, identified sequence variants (rs9291768, rs6874700, c.137C &gt; G (p.Ala46Gly)) associated with CBE. Here, we aimed to determine the molecular and functional consequences of these sequence variants and estimate the dependence of ISL1 protein on other predicted candidates. We used: (i) computational analysis of conserved sequence motifs to perform an evolutionary conservation analysis, based on a Bayesian algorithm, and (ii) computational 3D structural modeling. Furthermore, we looked into long non-coding RNAs (lncRNAs) residing within the ISL1 region, aiming to predict their targets. Our analysis suggests that the ISL1 protein specific N-terminal LIM domain (which harbors the variant c.137C &gt; G), limits its transcriptional ability, and might interfere with ISL1-estrogen receptor \u03b1 interactions. In conclusion, our analysis provides further useful insights about the ISL1 gene, which is involved in the formation of the BEEC, and in the development of the urinary bladder.<\/jats:p>","DOI":"10.3390\/genes9120609","type":"journal-article","created":{"date-parts":[[2018,12,5]],"date-time":"2018-12-05T12:22:00Z","timestamp":1544012520000},"page":"609","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Towards a Central Role of ISL1 in the Bladder Exstrophy\u2013Epispadias Complex (BEEC): Computational Characterization of Genetic Variants and Structural Modelling"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2216-5389","authenticated-orcid":false,"given":"Amit","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Neurology, University Clinic Bonn, 53105, Bonn, Germany"},{"name":"Department of Ophthalmology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tikam","family":"Dakal","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Mohanlal Sukhadia University Udaipur, 313001, Rajasthan, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2287-5281","authenticated-orcid":false,"given":"Michael","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, 53105 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5328-1243","authenticated-orcid":false,"given":"Holger","family":"Fr\u00f6hlich","sequence":"additional","affiliation":[{"name":"Bonn-Aachen International Center for IT, University of Bonn, 53115 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riya","family":"Mathur","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Manipal University Jaipur, 303007 Jaipur, Rajasthan, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3591-5265","authenticated-orcid":false,"given":"Heiko","family":"Reutter","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital of Bonn, 53127 Bonn, Germany"},{"name":"Department of Genomics, Life &amp; Brain Center, 53127 Bonn, Germany"},{"name":"Department of Neonatology and Pediatric Intensive Care, Children\u2019s Hospital, University of Bonn, 53113 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ebert, A.K., Reutter, H., Ludwig, M., and Rosch, W.H. 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