Posttranscriptional regulation of FAN1 by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington's disease
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 121(2024), 16 vom: 16. Apr., Seite e2322924121 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kim, Kyung-Hee [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.04.2024 Date Revised 26.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2322924121 |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Kim, Kyung-Hee |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Posttranscriptional regulation of FAN1 by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington's disease |
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| 500 | |a Date Revised 26.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Hong, Eun Pyo |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Yukyeong |e verfasserin |4 aut | |
| 700 | 1 | |a McLean, Zachariah L |e verfasserin |4 aut | |
| 700 | 1 | |a Elezi, Emanuela |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Ramee |e verfasserin |4 aut | |
| 700 | 1 | |a Kwak, Seung |e verfasserin |4 aut | |
| 700 | 1 | |a McAllister, Branduff |e verfasserin |4 aut | |
| 700 | 1 | |a Massey, Thomas H |e verfasserin |4 aut | |
| 700 | 1 | |a Lobanov, Sergey |e verfasserin |4 aut | |
| 700 | 1 | |a Holmans, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Orth, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Ciosi, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Monckton, Darren G |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Jeffrey D |e verfasserin |4 aut | |
| 700 | 1 | |a Lucente, Diane |e verfasserin |4 aut | |
| 700 | 1 | |a Wheeler, Vanessa C |e verfasserin |4 aut | |
| 700 | 1 | |a MacDonald, Marcy E |e verfasserin |4 aut | |
| 700 | 1 | |a Gusella, James F |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jong-Min |e verfasserin |4 aut | |
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