{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:05Z","timestamp":1787027825470,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004375","name":"Tel Aviv University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004375","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04mhzgx49","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Maxillofacial Surgery, Baruch Padeh Medical Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Juvenile Polyposis Syndrome (JPS) is an autosomal dominant disorder characterized by multiple gastrointestinal polyps and an increased risk of cancer, most commonly associated with mutations in the tumor suppressor gene Smad4. However, substantial phenotypic variability exists among individuals carrying identical mutations, suggesting the presence of genetic modifiers. In this study, we used the genetically diverse Collaborative Cross (CC) mouse population crossed with Smad4 knockout mice to identify loci influencing intestinal polyp development. A cohort of 260 F1 mice derived from 14 CC lines was assessed for polyp number and size across intestinal segments. Quantitative trait locus (QTL) mapping revealed several significant loci, including regions on chromosomes 16, 14, and 12, which were designated Ipsl1, Ipsl2, and Ipsl3 for Intestinal Polyposis Susceptibility locus (Ipsl), respectively, in the full population, as well as additional sex-specific loci in male and female cohorts. Pathway enrichment analysis of genes within these regions highlighted functional associations with immune signaling, ubiquitin\u2013proteasome degradation, and metabolic regulation. Candidate genes, including STAM2, PSMD6, NAMPT, and CACNB4, emerged as potential modifiers of polyp susceptibility. These findings highlight the complex genetic architecture underlying JPS phenotypes and provide candidate loci for future functional and translational investigations.<\/jats:p>","DOI":"10.3390\/cells15100853","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T12:15:07Z","timestamp":1778156107000},"page":"853","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mapping Genetic Modifiers of Polyp Formation in Smad4-Deficient Juvenile Polyposis Using the Collaborative Cross Mouse Population"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3530-1420","authenticated-orcid":false,"given":"Osayd","family":"Zohud","sequence":"first","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0144-575X","authenticated-orcid":false,"given":"Kreem","family":"Midlej","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5292-6778","authenticated-orcid":false,"given":"Iqbal M.","family":"Lone","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysar","family":"Nashef","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Poriya 1528001, Israel"},{"name":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel"},{"name":"Department of Oral and Maxillofacial Surgery, Meir Medical Center, Kfar Saba Affiliated to the Faculty of Medicine and Health Sciences, Tel-Aviv University, Kfar Saba 4428164, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imad","family":"Abu-Elnaaj","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Poriya 1528001, Israel"},{"name":"Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5525-206X","authenticated-orcid":false,"given":"Fuad A.","family":"Iraqi","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/ccr3.2616","article-title":"Juvenile Polyposis Syndrome","volume":"8","author":"Hussain","year":"2022","journal-title":"Clin. 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