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

Kim, Kyung-Hee, Hong, Eun Pyo, Shin, Jun Wan, Chao, Michael J., Loupe, Jacob, Gillis, Tammy, Mysore, Jayalakshmi S., Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612, Orth, Michael, Monckton, Darren G., Long, Jeffrey D., Kwak, Seung, Lee, Ramee, Gusella, James F., MacDonald, Marcy E. and Lee, Jong-Min 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. 10.1016/j.ajhg.2020.05.012

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Abstract

A recent genome-wide association study of Huntington’s 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 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 identified 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/suppression studies, knock out 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 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:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier (Cell Press)
ISSN:	0002-9297
Date of First Compliant Deposit:	21 May 2020
Date of Acceptance:	19 May 2020
Last Modified:	24 Nov 2024 21:15
URI:	https://orca.cardiff.ac.uk/id/eprint/131840

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