Exome sequencing of individuals with Huntington’s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset

McAllister, B. et al. (2022) Exome sequencing of individuals with Huntington’s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset. Nature Neuroscience, 25(4), pp. 446-457. (doi: 10.1038/s41593-022-01033-5) (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.

• Item Type: Articles
• Additional Information: We acknowledge the support of the Supercomputing Wales project, which is partly funded by the European Regional Development Fund via the Welsh Government. B.M. was supported by a PhD studentship from Cardiff University and an Alzheimer’s Research UK pump-priming award. J.D. was supported by a Wellcome Trust studentship (109088/Z/15A). J.F.G., M.E.M. and J.D.L. received support from National Institutes of Health grants NS091161 and NS082079 and from the CHDI Foundation. J.-M.L. received support from grant NS105709. V.C.W. received support from grant NS049206. J.S.P. received support from NS040068 to see PREDICT-HD participants. A.E.R. received support from the MRC, the Wellcome Trust, Horizon 2020, JPND and the B.R.A.I.N. unit, funded through Health and Care Research Wales. L.J., N.M.W. and P.H. were supported by an MRC Centre grant (MR/L010305/1). M.C., D.G.M., N.D.A., L.J. and T.H.M. have all received support from the CHDI Foundation. L.J. and T.H.M. received funding from the Brain Research Trust (201617-06). T.H.M. was supported by a Welsh Clinical Academic Training Fellowship, an MRC Clinical Training Fellowship (MR/P001629/1) and a Patrick Berthoud Charitable Trust Fellowship through the Association of British Neurologists.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Maxwell, Mr Alastair and Monckton, Professor Darren and Ciosi, Dr Marc
• Authors: McAllister, B., Donaldson, J., Binda, C. S., Powell, S., Chughtai, U., Edwards, G., Stone, J., Lobanov, S., Elliston, L., Schuhmacher, L.-N., Rees, E., Menzies, G., Ciosi, M., Maxwell, A., Chao, M. J., Hong, E. P., Lucente, D., Wheeler, V., Lee, J.-M., MacDonald, M. E., Long, J. D., Aylward, E. H., Landwehrmeyer, G. B., Rosser, A. E., Paulsen, J. S., Williams, N. M., Gusella, J. F., Monckton, D. G., Allen, N. D., Holmans, P., Jones, L., and Massey, T. H.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Nature Neuroscience
• Publisher: Nature Publishing Group
• ISSN: 1097-6256
• ISSN (Online): 1546-1726
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Nature Neuroscience 25(4):446-457
• Publisher Policy: Reproduced under a Creative Commons License