Posttranscriptional regulation of FAN1 by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington's disease.

Autor: Kim KH; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Hong EP; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.; Department of Neurology, Harvard Medical School, Boston, MA 02115., Lee Y; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.; Department of Neurology, Harvard Medical School, Boston, MA 02115., McLean ZL; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.; Department of Neurology, Harvard Medical School, Boston, MA 02115.; Medical and Population Genetics Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142., Elezi E; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114., Lee R; CHDI Foundation, Princeton, NJ 08540., Kwak S; CHDI Foundation, Princeton, NJ 08540., McAllister B; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.; Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom., Massey TH; Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom., Lobanov S; Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom., Holmans P; Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom., Orth M; University Hospital of Old Age Psychiatry and Psychotherapy, Bern University, CH-3000 Bern 60, Switzerland., Ciosi M; School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom., Monckton DG; School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom., Long JD; Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.; Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA 52242., Lucente D; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114., Wheeler VC; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.; Department of Neurology, Harvard Medical School, Boston, MA 02115., MacDonald ME; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.; Department of Neurology, Harvard Medical School, Boston, MA 02115.; Medical and Population Genetics Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142., Gusella JF; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.; Medical and Population Genetics Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142.; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115., Lee JM; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.; Department of Neurology, Harvard Medical School, Boston, MA 02115.; Medical and Population Genetics Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Apr 16; Vol. 121 (16), pp. e2322924121. Date of Electronic Publication: 2024 Apr 12.
DOI: 10.1073/pnas.2322924121
Abstrakt: 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.
Competing Interests: Competing interests statement:J.-M.L. consults for Life Edit Therapeutics and serves on the scientific advisory board of GenEdit Inc. J.F.G. was a Founder and Scientific Advisory Board member with a financial interest in Triplet Therapeutics Inc. His NIH-funded project is using genetic and genomic approaches to uncover other genes that significantly influence when diagnosable symptoms emerge and how rapidly they worsen in HD. The company was developing new therapeutic approaches to address triplet repeat disorders such as HD, myotonic dystrophy, and SCAs. J.F.G.’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. J.F.G. also consults for Transine Therapeutics Ltd and has been a consultant for Wave Life Sciences USA Inc., Biogen Inc., and Pfizer Inc. V.C.W. was a Scientific Advisory Board member of Triplet Therapeutics, Inc., a company developing new therapeutic approaches to address triplet repeat disorders such HD and myotonic dystrophy. Her financial interests in Triplet Therapeutics were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. She is a scientific advisory board member of LoQus23 Therapeutics and has provided paid consulting services to Alnylam, Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc. and Passage Bio. S.L. is currently employee of Illumina, Inc., a public company that develops and markets systems for genetic analysis. Within the last 5 y D.G.M. has been a scientific consultant and/or received an honoraria/grants from AMO Pharma, Dyne, F. Hoffman-La Roche, LoQus23, MOMA Therapeutics, Novartis, Ono Pharmaceuticals, Pfizer Pharmaceuticals, Rgenta Therpeutics, Sanofi, Sarepta Therapeutics Inc, Script Biosciences, Triplet Therapeutics, and Vertex Pharmaceuticals. D.G.M. also had research contracts with AMO Pharma and Vertex Pharmaceuticals. T.H.M. is an associate member of the scientific advisory board of LoQus23 Therapeutics Ltd.
Databáze: MEDLINE