{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T21:39:32Z","timestamp":1761514772086,"version":"3.41.2"},"reference-count":29,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T00:00:00Z","timestamp":1622678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Peutz\u2013Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disease resulting in multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation, and an increased risk of various types of cancer, and is caused by variations in the serine\/threonine protein kinase <jats:italic>STK11<\/jats:italic> (<jats:italic>LKB1<\/jats:italic>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>STK11<\/jats:italic> gene variations were identified by analyzing <jats:italic>STK11<\/jats:italic> cDNA and genomic DNA. Minigenes carrying the wild\u2010type and mutant sequences were subjected to in vitro splicing assay to dissect the features of these mutations. The different distribution of wild\u2010type and mutant protein in cells were tested by Immunofluorescence assays and the functional analysis of the variation were performed using Western blot.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel heterozygous splice\u2010acceptor site variation (c.921\u20102 A&gt;C) in intron 7 of the <jats:italic>STK11<\/jats:italic>\u00a0gene which is co\u2010segregates with the PJS phenotypes in the proband and all the affected family members and three previously reported variations (c.180C&gt;G, c.580G&gt;A, c.787_790del) were identified in the four families. The c.921\u20102 A&gt;C substitution resulted in the inactivation of a splice site and the utilization of a cryptic splice acceptor site surrounding exon 8, generating three different aberrant RNA transcripts, leading to frameshift translation and protein truncation. The results of minigenes indicated that the spliceosome can use a variety of 3\u2019 acceptor site sequences to pair with a given 5\u2019 donor site. The immunofluorescent visualization showed that the distribution of mutant STK11 was different from that of wild\u2010type STK11, suggesting the mutation may be the causative effect on the dysfunction of the mutant protein. The rescue experiments indicated that the failure of suppressing mTOR phosphorylation by shRNA STK11 could be eliminated by supply of wild\u2010type STK11 rather than mutant STK11.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified a novel heterozygous mutation (c.921\u20102 A&gt;C) in the <jats:italic>STK11<\/jats:italic> in a Chinese PJS family. Haploinsufficiency of STK11 might contribute to the pathogenesis of the disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1729","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T09:49:15Z","timestamp":1622800155000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A novel pathogenic splice site variation in <i>STK11<\/i> gene results in Peutz\u2013Jeghers syndrome"],"prefix":"10.1002","volume":"9","author":[{"given":"Na","family":"Zhao","sequence":"first","affiliation":[{"name":"Institutes of Biomedical Sciences Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education Shanxi University Taiyuan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huizhi","family":"Wu","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education Shanxi University Taiyuan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6137-6154","authenticated-orcid":false,"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education Shanxi University Taiyuan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology The First Affiliated Hospital of Shanxi Medical University Taiyuan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Dong","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education Shanxi University Taiyuan 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