{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T01:07:51Z","timestamp":1708564071306},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T00:00:00Z","timestamp":1708473600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T00:00:00Z","timestamp":1708473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003252","name":"Lund University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003252","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>DNA mismatch repair (MMR) is thought to contribute to the onset and progression of Huntington disease (HD) by promoting somatic expansion of the pathogenic CAG nucleotide repeat in the huntingtin gene (<jats:italic>HTT<\/jats:italic>). Here we have studied constitutional <jats:italic>HTT<\/jats:italic> CAG repeat size in two cohorts of individuals with Lynch syndrome (LS) carrying heterozygous loss-of-function variants in the MMR genes <jats:italic>MLH1<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u200912\/60; Lund cohort\/Bochum cohort, respectively), <jats:italic>MSH2<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u200915\/88), <jats:italic>MSH6<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u200921\/23), and controls (<jats:italic>n<\/jats:italic>\u2009=\u200919\/559). The sum of CAG repeats for both <jats:italic>HTT<\/jats:italic> alleles in each individual was calculated due to unknown segregation with the LS allele. In the larger Bochum cohort, the sum of CAG repeats was lower in the <jats:italic>MLH1<\/jats:italic> subgroup compared to controls (<jats:italic>MLH1<\/jats:italic> 35.40 CAG repeats\u2009\u00b1\u20093.6 vs. controls 36.89 CAG repeats\u2009\u00b1\u20094.5; <jats:italic>p<\/jats:italic>\u2009=\u20090.014). All LS genetic subgroups in the Bochum cohort displayed lower frequencies of unstable <jats:italic>HTT<\/jats:italic> intermediate alleles and lower <jats:italic>HTT<\/jats:italic> somatic CAG repeat expansion index values compared to controls. Collectively, our results indicate that MMR gene haploinsufficiency could have a restraining impact on constitutional <jats:italic>HTT<\/jats:italic> CAG repeat size and support the notion that the MMR pathway is a driver of nucleotide repeat expansion diseases.<\/jats:p>","DOI":"10.1038\/s41598-024-54277-5","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T13:02:18Z","timestamp":1708520538000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Attenuated huntingtin gene CAG nucleotide repeat size in individuals with Lynch syndrome"],"prefix":"10.1038","volume":"14","author":[{"given":"Karin","family":"Dalene Skarping","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larissa","family":"Arning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c5sa","family":"Peters\u00e9n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huu Phuc","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Gebre-Medhin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,2,21]]},"reference":[{"key":"54277_CR1","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/B978-0-444-63233-3.00009-9","volume":"147","author":"H Paulson","year":"2018","unstructured":"Paulson, H. Repeat expansion diseases. Handb. Clin. Neurol. 147, 105\u2013123. https:\/\/doi.org\/10.1016\/B978-0-444-63233-3.00009-9 (2018).","journal-title":"Handb. Clin. Neurol."},{"key":"54277_CR2","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-e","volume":"72","author":"The Huntington's Disease Collaborative Research Group","year":"1993","unstructured":"The Huntington\u2019s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. Cell 72, 971\u2013983. https:\/\/doi.org\/10.1016\/0092-8674(93)90585-e (1993).","journal-title":"Cell"},{"key":"54277_CR3","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/s41582-020-0389-4","volume":"16","author":"SJ Tabrizi","year":"2020","unstructured":"Tabrizi, S. J., Flower, M. D., Ross, C. A. & Wild, E. J. Huntington disease: New insights into molecular pathogenesis and therapeutic opportunities. Nat. Rev. Neurol. 16, 529\u2013546. https:\/\/doi.org\/10.1038\/s41582-020-0389-4 (2020).","journal-title":"Nat. Rev. Neurol."},{"key":"54277_CR4","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1097\/00005072-198511000-00003","volume":"44","author":"JP Vonsattel","year":"1985","unstructured":"Vonsattel, J. P. et al. Neuropathological classification of Huntington\u2019s disease. J. Neuropathol. Exp. Neurol. 44, 559\u2013577. https:\/\/doi.org\/10.1097\/00005072-198511000-00003 (1985).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"54277_CR5","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/j.1399-0004.2004.00241.x","volume":"65","author":"DR Langbehn","year":"2004","unstructured":"Langbehn, D. R. et al. A new model for prediction of the age of onset and penetrance for Huntington\u2019s disease based on CAG length. Clin. Genet. 65, 267\u2013277. https:\/\/doi.org\/10.1111\/j.1399-0004.2004.00241.x (2004).","journal-title":"Clin. Genet."},{"key":"54277_CR6","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1038\/s41436-020-0917-z","volume":"22","author":"H Findlay Black","year":"2020","unstructured":"Findlay Black, H. et al. Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range. Genet. Med. 22, 2108\u20132113. https:\/\/doi.org\/10.1038\/s41436-020-0917-z (2020).","journal-title":"Genet. Med."},{"key":"54277_CR7","doi-asserted-by":"publisher","unstructured":"Genetic Modifiers of Huntington\u2019s Disease (GeM-HD) Consortium. CAG Repeat Not Polyglutamine Length Determines Timing of Huntington's Disease Onset. Cell 178, 887\u2013900 e814. https:\/\/doi.org\/10.1016\/j.cell.2019.06.036 (2019).","DOI":"10.1016\/j.cell.2019.06.036"},{"key":"54277_CR8","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1016\/j.ajhg.2019.04.007","volume":"104","author":"GEB Wright","year":"2019","unstructured":"Wright, G. E. B. et al. Length of uninterrupted CAG, independent of polyglutamine size, results in increased somatic instability, hastening onset of Huntington disease. Am. J. Hum. Genet. 104, 1116\u20131126. https:\/\/doi.org\/10.1016\/j.ajhg.2019.04.007 (2019).","journal-title":"Am. J. Hum. Genet."},{"key":"54277_CR9","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1002\/ana.24656","volume":"79","author":"C Bettencourt","year":"2016","unstructured":"Bettencourt, C. et al. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases. Ann. Neurol. 79, 983\u2013990. https:\/\/doi.org\/10.1002\/ana.24656 (2016).","journal-title":"Ann. Neurol."},{"key":"54277_CR10","doi-asserted-by":"publisher","unstructured":"Genetic Modifiers of Huntington\u2019s Disease (GeM-HD) Consortium. Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. Cell 162, 516\u2013526. https:\/\/doi.org\/10.1016\/j.cell.2015.07.003 (2015).","DOI":"10.1016\/j.cell.2015.07.003"},{"key":"54277_CR11","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1093\/hmg\/ddy375","volume":"28","author":"R Goold","year":"2019","unstructured":"Goold, R. et al. FAN1 modifies Huntington\u2019s disease progression by stabilizing the expanded HTT CAG repeat. Hum. Mol. Genet. 28, 650\u2013661. https:\/\/doi.org\/10.1093\/hmg\/ddy375 (2019).","journal-title":"Hum. Mol. Genet."},{"key":"54277_CR12","doi-asserted-by":"publisher","first-page":"3859","DOI":"10.1093\/hmg\/ddx286","volume":"26","author":"JM Lee","year":"2017","unstructured":"Lee, J. M. et al. A modifier of Huntington\u2019s disease onset at the MLH1 locus. Hum. Mol. Genet. 26, 3859\u20133867. https:\/\/doi.org\/10.1093\/hmg\/ddx286 (2017).","journal-title":"Hum. Mol. Genet."},{"key":"54277_CR13","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/S1474-4422(17)30161-8","volume":"16","author":"DJH Moss","year":"2017","unstructured":"Moss, D. J. H. et al. Identification of genetic variants associated with Huntington\u2019s disease progression: A genome-wide association study. Lancet Neurol. 16, 701\u2013711. https:\/\/doi.org\/10.1016\/S1474-4422(17)30161-8 (2017).","journal-title":"Lancet Neurol."},{"key":"54277_CR14","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3233\/JHD-200438","volume":"10","author":"RR Iyer","year":"2021","unstructured":"Iyer, R. R. & Pluciennik, A. DNA mismatch repair and its role in Huntington\u2019s disease. J. Huntingtons Dis. 10, 75\u201394. https:\/\/doi.org\/10.3233\/JHD-200438 (2021).","journal-title":"J. Huntingtons Dis."},{"key":"54277_CR15","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1093\/oxfordjournals.molbev.a040442","volume":"4","author":"G Levinson","year":"1987","unstructured":"Levinson, G. & Gutman, G. A. Slipped-strand mispairing: A major mechanism for DNA sequence evolution. Mol. Biol. Evol. 4, 203\u2013221. https:\/\/doi.org\/10.1093\/oxfordjournals.molbev.a040442 (1987).","journal-title":"Mol. Biol. Evol."},{"key":"54277_CR16","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1111\/apt.16826","volume":"55","author":"K Curtius","year":"2022","unstructured":"Curtius, K., Gupta, S. & Boland, C. R. Review article: Lynch Syndrome-a mechanistic and clinical management update. Aliment Pharmacol. Ther. 55, 960\u2013977. https:\/\/doi.org\/10.1111\/apt.16826 (2022).","journal-title":"Aliment Pharmacol. Ther."},{"key":"54277_CR17","doi-asserted-by":"publisher","unstructured":"Mouro Pinto, R. et al. Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in spinocerebellar ataxia type 1. Hum. Mol. Genet. 29, 2551\u20132567. https:\/\/doi.org\/10.1093\/hmg\/ddaa139 (2020).","DOI":"10.1093\/hmg\/ddaa139"},{"key":"54277_CR18","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1136\/jmedgenet-2020-107627","volume":"59","author":"M Aronson","year":"2022","unstructured":"Aronson, M. et al. Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): Recommendations from the international consensus working group. J. Med. Genet. 59, 318\u2013327. https:\/\/doi.org\/10.1136\/jmedgenet-2020-107627 (2022).","journal-title":"J. Med. Genet."},{"key":"54277_CR19","doi-asserted-by":"publisher","first-page":"2710","DOI":"10.1038\/s41467-022-29920-2","volume":"13","author":"BCH Lee","year":"2022","unstructured":"Lee, B. C. H. et al. Mutational landscape of normal epithelial cells in Lynch Syndrome patients. Nat. Commun. 13, 2710. https:\/\/doi.org\/10.1038\/s41467-022-29920-2 (2022).","journal-title":"Nat. Commun."},{"key":"54277_CR20","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/S1474-4422(21)00462-2","volume":"21","author":"K Ibanez","year":"2022","unstructured":"Ibanez, K. et al. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: A retrospective diagnostic accuracy and prospective clinical validation study. Lancet Neurol. 21, 234\u2013245. https:\/\/doi.org\/10.1016\/S1474-4422(21)00462-2 (2022).","journal-title":"Lancet Neurol."},{"key":"54277_CR21","doi-asserted-by":"publisher","first-page":"9853","DOI":"10.1038\/s41598-020-66643-0","volume":"10","author":"J Sundblom","year":"2020","unstructured":"Sundblom, J. et al. High frequency of intermediary alleles in the HTT gene in Northern Sweden\u2014The Swedish Huntingtin Alleles and Phenotype (SHAPE) study. Sci. Rep. 10, 9853. https:\/\/doi.org\/10.1038\/s41598-020-66643-0 (2020).","journal-title":"Sci. Rep."},{"key":"54277_CR22","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3233\/JHD-200429","volume":"10","author":"DG Monckton","year":"2021","unstructured":"Monckton, D. G. The contribution of somatic expansion of the CAG repeat to symptomatic development in Huntington\u2019s Disease: A historical perspective. J. Huntingtons Dis. 10, 7\u201333. https:\/\/doi.org\/10.3233\/JHD-200429 (2021).","journal-title":"J. Huntingtons Dis."},{"key":"54277_CR23","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.nbd.2008.09.014","volume":"33","author":"E Dragileva","year":"2009","unstructured":"Dragileva, E. et al. Intergenerational and striatal CAG repeat instability in Huntington\u2019s disease knock-in mice involve different DNA repair genes. Neurobiol. Dis. 33, 37\u201347. https:\/\/doi.org\/10.1016\/j.nbd.2008.09.014 (2009).","journal-title":"Neurobiol. Dis."},{"key":"54277_CR24","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/70598","volume":"23","author":"K Manley","year":"1999","unstructured":"Manley, K., Shirley, T. L., Flaherty, L. & Messer, A. Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat. Genet. 23, 471\u2013473. https:\/\/doi.org\/10.1038\/70598 (1999).","journal-title":"Nat. Genet."},{"key":"54277_CR25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003930","volume":"9","author":"RM Pinto","year":"2013","unstructured":"Pinto, R. M. et al. Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington\u2019s disease mice: genome-wide and candidate approaches. PLoS Genet. 9, e1003930. https:\/\/doi.org\/10.1371\/journal.pgen.1003930 (2013).","journal-title":"PLoS Genet."},{"key":"54277_CR26","doi-asserted-by":"publisher","first-page":"3044","DOI":"10.1093\/hmg\/ddaa196","volume":"29","author":"JM Loupe","year":"2020","unstructured":"Loupe, J. M. et al. Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington\u2019s disease knock-in mice is blocked by Mlh1 knock-out. Hum. Mol. Genet. 29, 3044\u20133053. https:\/\/doi.org\/10.1093\/hmg\/ddaa196 (2020).","journal-title":"Hum. Mol. Genet."},{"key":"54277_CR27","doi-asserted-by":"publisher","unstructured":"Porro, A. et al. FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG\/CTG repeats. Sci. Adv. 7. https:\/\/doi.org\/10.1126\/sciadv.abf7906 (2021).","DOI":"10.1126\/sciadv.abf7906"},{"key":"54277_CR28","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405\u2013424. https:\/\/doi.org\/10.1038\/gim.2015.30 (2015).","journal-title":"Genet. Med."},{"key":"54277_CR29","unstructured":"The International Society for Gastrointestinal Hereditary Tumours Data Base, http:\/\/insight-database.org\/."},{"key":"54277_CR30","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1038\/ejhg.2012.200","volume":"21","author":"M Losekoot","year":"2013","unstructured":"Losekoot, M. et al. EMQN\/CMGS best practice guidelines for the molecular genetic testing of Huntington disease. Eur. J. Hum. Genet. 21, 480\u2013486. https:\/\/doi.org\/10.1038\/ejhg.2012.200 (2013).","journal-title":"Eur. J. Hum. Genet."},{"key":"54277_CR31","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1006\/geno.1994.1061","volume":"19","author":"O Riess","year":"1994","unstructured":"Riess, O. et al. Precise mapping of the brain alpha 2-adrenergic receptor gene within chromosome 4p16. Genomics 19, 298\u2013302. https:\/\/doi.org\/10.1006\/geno.1994.1061 (1994).","journal-title":"Genomics"},{"key":"54277_CR32","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1093\/hmg\/2.10.1713","volume":"2","author":"DC Rubinsztein","year":"1993","unstructured":"Rubinsztein, D. C., Barton, D. E., Davison, B. C. & Ferguson-Smith, M. A. Analysis of the huntingtin gene reveals a trinucleotide-length polymorphism in the region of the gene that contains two CCG-rich stretches and a correlation between decreased age of onset of Huntington\u2019s disease and CAG repeat number. Hum. Mol. Genet. 2, 1713\u20131715. https:\/\/doi.org\/10.1093\/hmg\/2.10.1713 (1993).","journal-title":"Hum. Mol. Genet."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-54277-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-54277-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-54277-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T13:20:03Z","timestamp":1708521603000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-54277-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,21]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["54277"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-54277-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,21]]},"assertion":[{"value":"14 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4300"}}