{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:10:38Z","timestamp":1791220238880,"version":"4.1.0"},"reference-count":73,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000887","name":"Huntington's Disease Society of America","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000887","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS049206"],"award-info":[{"award-number":["NS049206"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Dake Family Foundation"},{"DOI":"10.13039\/100002108","name":"Friedreich's Ataxia Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018576","name":"Harrington Discovery Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100018576","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Somatic expansion of the CAG repeat tract that causes Huntington's disease (HD) is thought to contribute to the rate of disease pathogenesis. Therefore, factors influencing repeat expansion are potential therapeutic targets. Genes in the DNA mismatch repair pathway are critical drivers of somatic expansion in HD mouse models. Here, we have tested, using genetic and pharmacological approaches, the role of the endonuclease domain of the mismatch repair protein MLH3 in somatic CAG expansion in HD mice and patient cells. A point mutation in the MLH3 endonuclease domain completely eliminated CAG expansion in the brain and peripheral tissues of a HD knock-in mouse model (HttQ111). To test whether the MLH3 endonuclease could be manipulated pharmacologically, we delivered splice switching oligonucleotides in mice to redirect Mlh3 splicing to exclude the endonuclease domain. Splice redirection to an isoform lacking the endonuclease domain was associated with reduced CAG expansion. Finally, CAG expansion in HD patient-derived primary fibroblasts was also significantly reduced by redirecting MLH3 splicing to the endogenous endonuclease domain-lacking isoform. These data indicate the potential of targeting the MLH3 endonuclease domain to slow somatic CAG repeat expansion in HD, a therapeutic strategy that may be applicable across multiple repeat expansion disorders.<\/jats:p>","DOI":"10.1093\/nar\/gkab152","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T15:29:28Z","timestamp":1614094168000},"page":"3907-3918","source":"Crossref","is-referenced-by-count":49,"title":["Somatic CAG expansion in Huntington's disease is dependent on the MLH3 endonuclease domain, which can be excluded via splice redirection"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3968-9637","authenticated-orcid":false,"given":"Jennie C L","family":"Roy","sequence":"first","affiliation":[{"name":"Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Vitalo","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114,\u00a0USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02115,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa A","family":"Andrew","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduarda","family":"Mota-Silva","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Kovalenko","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Burch","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6822-6562","authenticated-orcid":false,"given":"Anh M","family":"Nhu","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula E","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Cornell University, Ithaca, NY\u00a014853,\u00a0USA"},{"name":"Center for Reproductive Genomics, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ed","family":"Grabczyk","sequence":"additional","affiliation":[{"name":"Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa\u00a0C","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114,\u00a0USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02115,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6744-2805","authenticated-orcid":false,"given":"Ricardo","family":"Mouro\u00a0Pinto","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114,\u00a0USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02115,\u00a0USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"2021070811523372100_B1","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes","volume":"72","author":"Huntington\u2019s Disease Collaborative Research Group","year":"1993","journal-title":"Cell"},{"key":"2021070811523372100_B2","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/00005072-198511000-00003","article-title":"Neuropathological classification of Huntington's disease","volume":"44","author":"Vonsattel","year":"1985","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"2021070811523372100_B3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/ene.13413","article-title":"Huntington's disease: a clinical review","volume":"25","author":"McColgan","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"2021070811523372100_B4","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.1093\/hmg\/ddg352","article-title":"Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis","volume":"12","author":"Kennedy","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"2021070811523372100_B5","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1093\/hmg\/ddm054","article-title":"Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain","volume":"16","author":"Shelbourne","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"2021070811523372100_B6","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1073\/pnas.0800048105","article-title":"DNA instability in postmitotic neurons","volume":"105","author":"Gonitel","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021070811523372100_B7","doi-asserted-by":"crossref","first-page":"3039","DOI":"10.1093\/hmg\/ddp242","article-title":"Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset","volume":"18","author":"Swami","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"2021070811523372100_B8","doi-asserted-by":"crossref","first-page":"3044","DOI":"10.1093\/hmg\/ddaa196","article-title":"Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington's disease knock-in mice is blocked by Mlh1 knock-out","volume":"29","author":"Loupe","year":"2020","journal-title":"Hum. Mol. 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