한빛사 논문
Massachusetts General Hospital / Harvard Medical School, University of Ulm, the Broad Institute of MIT and Harvard
Kyung-Hee Kim1,2, Eun Pyo Hong1,2, Jun Wan Shin1,2, Michael J. Chao1,2, Jacob Loupe1,2, Tammy Gillis1, Jayalakshmi S. Mysore1, Peter Holmans3,4, Lesley Jones3,4, Michael Orth4,5, Darren G. Monckton4,6, Jeffrey D. Long4,7,8, Seung Kwak4,9, Ramee Lee9, James F. Gusella1,4,10,11, Marcy E. MacDonald1,2,4,10, Jong-MinLee1,2,4,10,*
1Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
2Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
3Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK
4The GeM-HD consortium, University of Ulm, Ulm 89081, Germany
5Department of Neurology, University of Ulm, Ulm 89081, Germany
6Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
7Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa 52242, USA
8Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
9CHDI Foundation, Princeton, NJ 08540, USA
10Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA
11Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
*Corresponding author
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.
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