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During the screening of a clinical exome sequencing database, nine SIM2 non-synonymous mutations were found which were subsequently investigated for impaired function using cell-based reporter gene assays. Many of these human variants attenuated abilities to activate transcription and were further characterized to determine the mechanisms underpinning their deficiencies. These included impaired partner protein dimerization, reduced DNA binding, and reduced expression and nuclear localization. This study highlighted several SIM2 variants found in patients with disabilities and validated a candidate set as potentially contributing to pathology.<\/jats:p>","DOI":"10.1042\/bcj20220209","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T11:13:17Z","timestamp":1655896397000},"page":"1441-1454","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Characterization of functionally deficient SIM2 variants found in patients with neurological phenotypes"],"prefix":"10.1042","volume":"479","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7962-7698","authenticated-orcid":false,"given":"Emily L.","family":"Button","sequence":"first","affiliation":[{"name":"1Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Rossi","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"McDougal","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6919-1824","authenticated-orcid":false,"given":"John B.","family":"Bruning","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia"},{"name":"2Institute of Photonics and Advanced Sensing, School of Biological Sciences, University of Adelaide, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Peet","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Bersten","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill A.","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, U.S.A."},{"name":"4Baylor Genetics Laboratories, Houston, TX, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murray L.","family":"Whitelaw","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2022,7,13]]},"reference":[{"key":"2022071314365556700_BCJ-2022-0209C1","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/nrc3621","article-title":"bHLH-PAS proteins in cancer","volume":"13","year":"2013","journal-title":"Nat. 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