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

McAllister, Branduff, Donaldson, Jasmine, Binda, Caroline S., Powell, Sophie, Chughtai, Uroosa, Stone, Joseph, Lobanov, Sergey, Elliston, Linda, Schuhmacher, Laura-Nadine, Rees, Elliott, Menzies, Georgina, Ciosi, Marc, Maxwell, Alastair, Chao, Michael J., Hong, Eun Pyo, Lucente, Diane, Wheeler, Vanessa, Lee, Jong-Min, MacDonald, Marcy E., Long, Jeffrey D., Aylward, Elizabeth H., Landwehrmeyer, G. Bernhard, Rosser, Anne E., Paulsen, Jane S., Williams, Nigel M., Gusella, James F., Monckton, Darren G., Allen, Nicholas D., Holmans, Peter and Massey, Thomas H. (2022) Exome sequencing of individuals with Huntington’s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset. Nature Neuroscience, 25, 446–457. (doi:10.1038/s41593-022-01033-5).

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.

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Contributors

Author: Sophie Powell

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