FAN1 nuclease activity affects CAG expansion and age at onset of Huntington's disease
Caroline S Binda,
Michael J Chao,
Eun Pyo Hong,
Marcy E MacDonald,
Jeffrey D. Long,
Elizabeth H Aylward,
G. Bernhard Landwehrmeyer,
Anne E Rosser,
Registry Investigators EHDN,
Jane S Paulsen,
PREDICT investigators HSG,
Nigel M Williams,
James F. Gusella,
Darren G. Monckton,
Nicholas D Allen,
Thomas H Massey
Posted 14 Apr 2021
bioRxiv DOI: 10.1101/2021.04.13.439716
Posted 14 Apr 2021
The age at onset of motor symptoms in Huntington disease (HD) is driven by HTT CAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior 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 these variants 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 comparable to those observed with complete FAN1 knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.
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