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Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects.
Am J Hum Genet. 2020 Jul 02; 107(1):96-110.AJ

Abstract

A recent genome-wide association study of Huntington disease (HD) implicated genes involved in DNA maintenance processes as modifiers of onset, including multiple genome-wide significant signals in a chr15 region containing the DNA repair gene Fanconi-Associated Nuclease 1 (FAN1). Here, we have carried out detailed genetic, molecular, and cellular investigation of the modifiers at this locus. We find that missense changes within or near the DNA-binding domain (p.Arg507His and p.Arg377Trp) reduce FAN1's DNA-binding activity and its capacity to rescue mitomycin C-induced cytotoxicity, accounting for two infrequent onset-hastening modifier signals. We also idenified a third onset-hastening modifier signal whose mechanism of action remains uncertain but does not involve an amino acid change in FAN1. We present additional evidence that a frequent onset-delaying modifier signal does not alter FAN1 coding sequence but is associated with increased FAN1 mRNA expression in the cerebral cortex. Consistent with these findings and other cellular overexpression and/or suppression studies, knockout of FAN1 increased CAG repeat expansion in HD-induced pluripotent stem cells. Together, these studies support the process of somatic CAG repeat expansion as a therapeutic target in HD, and they clearly indicate that multiple genetic variations act by different means through FAN1 to influence HD onset in a manner that is largely additive, except in the rare circumstance that two onset-hastening alleles are present. Thus, an individual's particular combination of FAN1 haplotypes may influence their suitability for HD clinical trials, particularly if the therapeutic agent aims to reduce CAG repeat instability.

Authors+Show Affiliations

Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK; The GeM-HD consortium, University of Ulm, Ulm 89081, Germany.Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK; The GeM-HD consortium, University of Ulm, Ulm 89081, Germany.The GeM-HD consortium, University of Ulm, Ulm 89081, Germany; Department of Neurology, University of Ulm, Ulm 89081, Germany.The GeM-HD consortium, University of Ulm, Ulm 89081, Germany; Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.The GeM-HD consortium, University of Ulm, Ulm 89081, Germany; Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa 52242, USA; Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.The GeM-HD consortium, University of Ulm, Ulm 89081, Germany; CHDI Foundation, Princeton, NJ 08540, USA.CHDI Foundation, Princeton, NJ 08540, USA.Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; The GeM-HD consortium, University of Ulm, Ulm 89081, Germany; Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; The GeM-HD consortium, University of Ulm, Ulm 89081, Germany; Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA.Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; The GeM-HD consortium, University of Ulm, Ulm 89081, Germany; Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA. Electronic address: jlee51@mgh.harvard.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32589923

Citation

Kim, Kyung-Hee, et al. "Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects." American Journal of Human Genetics, vol. 107, no. 1, 2020, pp. 96-110.
Kim KH, Hong EP, Shin JW, et al. Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects. Am J Hum Genet. 2020;107(1):96-110.
Kim, K. H., Hong, E. P., Shin, J. W., Chao, M. J., Loupe, J., Gillis, T., Mysore, J. S., Holmans, P., Jones, L., Orth, M., Monckton, D. G., Long, J. D., Kwak, S., Lee, R., Gusella, J. F., MacDonald, M. E., & Lee, J. M. (2020). Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects. American Journal of Human Genetics, 107(1), 96-110. https://doi.org/10.1016/j.ajhg.2020.05.012
Kim KH, et al. Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects. Am J Hum Genet. 2020 Jul 2;107(1):96-110. PubMed PMID: 32589923.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects. AU - Kim,Kyung-Hee, AU - Hong,Eun Pyo, AU - Shin,Jun Wan, AU - Chao,Michael J, AU - Loupe,Jacob, AU - Gillis,Tammy, AU - Mysore,Jayalakshmi S, AU - Holmans,Peter, AU - Jones,Lesley, AU - Orth,Michael, AU - Monckton,Darren G, AU - Long,Jeffrey D, AU - Kwak,Seung, AU - Lee,Ramee, AU - Gusella,James F, AU - MacDonald,Marcy E, AU - Lee,Jong-Min, Y1 - 2020/06/25/ PY - 2020/03/18/received PY - 2020/05/18/accepted PY - 2021/01/02/pmc-release PY - 2020/6/27/pubmed PY - 2020/6/27/medline PY - 2020/6/27/entrez KW - DNA binding KW - FAN1 KW - Huntington's disease KW - genetic modifiers SP - 96 EP - 110 JF - American journal of human genetics JO - Am. J. Hum. Genet. VL - 107 IS - 1 N2 - A recent genome-wide association study of Huntington disease (HD) implicated genes involved in DNA maintenance processes as modifiers of onset, including multiple genome-wide significant signals in a chr15 region containing the DNA repair gene Fanconi-Associated Nuclease 1 (FAN1). Here, we have carried out detailed genetic, molecular, and cellular investigation of the modifiers at this locus. We find that missense changes within or near the DNA-binding domain (p.Arg507His and p.Arg377Trp) reduce FAN1's DNA-binding activity and its capacity to rescue mitomycin C-induced cytotoxicity, accounting for two infrequent onset-hastening modifier signals. We also idenified a third onset-hastening modifier signal whose mechanism of action remains uncertain but does not involve an amino acid change in FAN1. We present additional evidence that a frequent onset-delaying modifier signal does not alter FAN1 coding sequence but is associated with increased FAN1 mRNA expression in the cerebral cortex. Consistent with these findings and other cellular overexpression and/or suppression studies, knockout of FAN1 increased CAG repeat expansion in HD-induced pluripotent stem cells. Together, these studies support the process of somatic CAG repeat expansion as a therapeutic target in HD, and they clearly indicate that multiple genetic variations act by different means through FAN1 to influence HD onset in a manner that is largely additive, except in the rare circumstance that two onset-hastening alleles are present. Thus, an individual's particular combination of FAN1 haplotypes may influence their suitability for HD clinical trials, particularly if the therapeutic agent aims to reduce CAG repeat instability. SN - 1537-6605 UR - https://www.unboundmedicine.com/medline/citation/32589923/Genetic_and_Functional_Analyses_Point_to_FAN1_as_the_Source_of_Multiple_Huntington_Disease_Modifier_Effects L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(20)30159-2 DB - PRIME DP - Unbound Medicine ER -
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