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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,16]]},"abstract":"<jats:p>\n                    Many Mendelian disorders, such as Huntington\u2019s disease (HD) and spinocerebellar ataxias, arise from expansions of CAG trinucleotide repeats. Despite the clear genetic causes, additional genetic factors may influence the rate of those monogenic disorders. Notably, genome-wide association studies discovered somewhat expected modifiers, particularly mismatch repair genes involved in the CAG repeat instability, impacting age at onset of HD. Strikingly,\n                    <jats:italic>FAN1<\/jats:italic>\n                    , previously unrelated to repeat instability, produced the strongest HD modification signals. Diverse\n                    <jats:italic>FAN1<\/jats:italic>\n                    haplotypes independently modify HD, with rare genetic variants diminishing DNA binding or nuclease activity of the FAN1 protein, hastening HD onset. However, the mechanism behind the frequent and the most significant onset-delaying\n                    <jats:italic>FAN1<\/jats:italic>\n                    haplotype lacking missense variations has remained elusive. Here, we illustrated that a microRNA acting on 3\u2032-UTR (untranslated region) SNP rs3512, rather than transcriptional regulation, is responsible for the significant\n                    <jats:italic>FAN1<\/jats:italic>\n                    expression quantitative trait loci signal and allelic imbalance in\n                    <jats:italic>FAN1<\/jats:italic>\n                    messenger ribonucleic acid (mRNA), accounting for the most significant and frequent onset-delaying modifier haplotype in HD. Specifically, miR-124-3p selectively targets the reference allele at rs3512, diminishing the stability of\n                    <jats:italic>FAN1<\/jats:italic>\n                    mRNA harboring that allele and consequently reducing its levels. Subsequent validation analyses, including the use of antagomir and 3\u2032-UTR reporter vectors with swapped alleles, confirmed the specificity of miR-124-3p at rs3512. Together, these findings indicate that the alternative allele at rs3512 renders the\n                    <jats:italic>FAN1<\/jats:italic>\n                    mRNA less susceptible to miR-124-3p-mediated posttranscriptional regulation, resulting in increased FAN1 levels and a subsequent delay in HD onset by mitigating CAG repeat instability.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2322924121","type":"journal-article","created":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T12:48:15Z","timestamp":1712926095000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["Posttranscriptional regulation of\n                    <i>FAN1<\/i>\n                    by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington\u2019s disease"],"prefix":"10.1073","volume":"121","author":[{"given":"Kyung-Hee","family":"Kim","sequence":"first","affiliation":[{"name":"Center for Genomic Medicine, 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Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Massey","sequence":"additional","affiliation":[{"name":"Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Lobanov","sequence":"additional","affiliation":[{"name":"Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Holmans","sequence":"additional","affiliation":[{"name":"Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Orth","sequence":"additional","affiliation":[{"name":"University Hospital of Old Age Psychiatry and Psychotherapy, Bern University, CH-3000 Bern 60, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ciosi","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8298-8264","authenticated-orcid":false,"given":"Darren G.","family":"Monckton","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D.","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242"},{"name":"Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA 52242"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Lucente","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa C.","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcy 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