Genetic and functional analyses point to FAN1 as the source of multiple Huntington disease modifier effects

Kim, K.-H. et al. (2020) Genetic and functional analyses point to FAN1 as the source of multiple Huntington disease modifier effects. American Journal of Human Genetics, 107(1), pp. 96-110. (doi: 10.1016/j.ajhg.2020.05.012) (PMID:32589923) (PMCID:PMC7332667)

[img] Text
220282.pdf - Accepted Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

854kB

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.

Item Type:Articles
Additional Information:This research was funded by National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) grants NS091161, NS105709, and NS049206, by an anonymous donor, and by the Cure Huntington's Disease Initiative (CHDI) Foundation.
Keywords:DNA binding, FAN1, Huntington's disease, genetic modifiers.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Monckton, Professor Darren
Authors: 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., and Lee, J.-M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:American Journal of Human Genetics
Publisher:Elsevier (Cell Press)
ISSN:0002-9297
ISSN (Online):1537-6605
Published Online:25 June 2020
Copyright Holders:Copyright © 2020 American Society of Human Genetics
First Published:First published in American Journal of Human Genetics 107(1): 96-110
Publisher Policy:Reproduced in accordance with the publisher copyright policy
Data DOI:10.5061/dryad.5d4s2r8

University Staff: Request a correction | Enlighten Editors: Update this record