Journal article
Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects
American journal of human genetics, Vol.107(1), pp.96-110
07/02/2020
DOI: 10.1016/j.ajhg.2020.05.012
PMCID: PMC7332667
PMID: 32589923
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.
Details
- Title: Subtitle
- Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects
- Creators
- Kyung-Hee Kim - Massachusetts General HospitalEun Pyo Hong - Massachusetts General HospitalJun Wan Shin - Massachusetts General HospitalMichael J. Chao - Massachusetts General HospitalJacob Loupe - Massachusetts General HospitalTammy Gillis - Massachusetts General HospitalJayalakshmi S. Mysore - Massachusetts General HospitalPeter Holmans - Cardiff UniversityLesley Jones - Cardiff UniversityMichael Orth - Universität UlmDarren G. Monckton - University of GlasgowJeffrey D. Long - University of IowaSeung Kwak - CHDI FoundationRamee Lee - CHDI FoundationJames F. Gusella - Massachusetts General HospitalMarcy E. MacDonald - Massachusetts General HospitalJong-Min Lee - Massachusetts Gen Hosp, Ctr Genom Med, Mol Neurogenet Unit, Boston, MA 02114 USA
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.107(1), pp.96-110
- DOI
- 10.1016/j.ajhg.2020.05.012
- PMID
- 32589923
- PMCID
- PMC7332667
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier
- Number of pages
- 15
- Grant note
- Cure Huntington's Disease Initiative (CHDI) Foundation NS091161; NS105709; NS049206 / National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
- Language
- English
- Date published
- 07/02/2020
- Academic Unit
- Psychiatry; Biostatistics
- Record Identifier
- 9984280869702771
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