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조회434

Massachusetts General Hospital / Harvard Medical School

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Proc. Natl. Acad. Sci. USA, Apr 16 2024, 121 (16) | https://doi.org/10.1073/pnas.2322924121 Posttranscriptional regulation of FAN1 by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington's disease

Kyung-Hee Kim ^{1 2}, Eun Pyo Hong ^{1 2}, Yukyeong Lee ^{1 2}, Zachariah L McLean ^{1 2 3}, Emanuela Elezi ¹, Ramee Lee ⁴, Seung Kwak ⁴, Branduff McAllister ^{1 5}, Thomas H Massey ⁵, Sergey Lobanov ⁵, Peter Holmans ⁵, Michael Orth ⁶, Marc Ciosi ⁷, Darren G Monckton ⁷, Jeffrey D Long ^{8 9}, Diane Lucente ¹, Vanessa C Wheeler ^{1 2}, Marcy E MacDonald ^{1 2 3}, James F Gusella^{1 3 10}, Jong-Min Lee ^{1 2 3 *}

¹Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.

²Department of Neurology, Harvard Medical School, Boston, MA 02115.

³Medical and Population Genetics Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142.

⁴CHDI Foundation, Princeton, NJ 08540.

⁵Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom.

⁶University Hospital of Old Age Psychiatry and Psychotherapy, Bern University, CH-3000 Bern 60, Switzerland.

⁷School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom.

⁸Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.

⁹Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA 52242.

¹⁰Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.

^*Corresponding author: correspondence to Jong-Min Lee

Abstract

Many Mendelian disorders, such as Huntington's 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, FAN1, previously unrelated to repeat instability, produced the strongest HD modification signals. Diverse FAN1 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 FAN1 haplotype lacking missense variations has remained elusive. Here, we illustrated that a microRNA acting on 3'-UTR (untranslated region) SNP rs3512, rather than transcriptional regulation, is responsible for the significant FAN1 expression quantitative trait loci signal and allelic imbalance in FAN1 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 FAN1 mRNA harboring that allele and consequently reducing its levels. Subsequent validation analyses, including the use of antagomir and 3'-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 FAN1 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.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-16)
연구진국외 연구진
분야 생명과학 > 유전학

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