Journal article
Exome sequencing of individuals with Huntington's disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset
Nature neuroscience, Vol.25(4), pp.446-457
04/2022
DOI: 10.1038/s41593-022-01033-5
PMCID: PMC8986535
PMID: 35379994
Abstract
The age at onset of motor symptoms in Huntington's disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with complete FAN1 knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.
Details
- Title: Subtitle
- Exome sequencing of individuals with Huntington's disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset
- Creators
- Branduff McAllister - Cardiff UniversityJasmine Donaldson - Cardiff UniversityCaroline S Binda - Cardiff UniversitySophie Powell - Cardiff UniversityUroosa Chughtai - Cardiff UniversityGareth Edwards - Cardiff UniversityJoseph Stone - Cardiff UniversitySergey Lobanov - Cardiff UniversityLinda Elliston - Cardiff UniversityLaura-Nadine Schuhmacher - Cardiff UniversityElliott Rees - Cardiff UniversityGeorgina Menzies - Cardiff UniversityMarc Ciosi - University of GlasgowAlastair Maxwell - University of GlasgowMichael J Chao - Massachusetts General HospitalEun Pyo Hong - Massachusetts General HospitalDiane Lucente - Massachusetts General HospitalVanessa Wheeler - Massachusetts General HospitalJong-Min Lee - Broad InstituteMarcy E MacDonald - Broad InstituteJeffrey D Long - University of IowaElizabeth H Aylward - Seattle Children's Research InstituteG Bernhard Landwehrmeyer - Universität UlmAnne E Rosser - Cardiff UniversityJane S Paulsen - University of Wisconsin–MadisonNigel M Williams - Cardiff UniversityJames F Gusella - Broad InstituteDarren G Monckton - University of GlasgowNicholas D Allen - Cardiff UniversityPeter Holmans - Cardiff UniversityLesley Jones - Cardiff UniversityThomas H Massey - Cardiff UniversityPREDICT-HD Investigators of the Huntington Study Group
- Resource Type
- Journal article
- Publication Details
- Nature neuroscience, Vol.25(4), pp.446-457
- DOI
- 10.1038/s41593-022-01033-5
- PMID
- 35379994
- PMCID
- PMC8986535
- NLM abbreviation
- Nat Neurosci
- ISSN
- 1097-6256
- eISSN
- 1546-1726
- Grant note
- MR/P001629/1 / RCUK | Medical Research Council (MRC) R01 NS040068 / NINDS NIH HHS Wellcome Trust MR/L010305/1 / RCUK | Medical Research Council (MRC) R01 NS091161 / NINDS NIH HHS R01 NS049206 / NINDS NIH HHS U01 NS082079 / NINDS NIH HHS 201617-06 / Brain Research Trust (BRT) R01 NS105709 / NINDS NIH HHS
- Language
- English
- Date published
- 04/2022
- Academic Unit
- Psychiatry; Psychological and Brain Sciences; Biostatistics
- Record Identifier
- 9984280879402771
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