Unknown

Dataset Information

0

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


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.

SUBMITTER: McAllister B 

PROVIDER: S-EPMC8986535 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

McAllister Branduff B   Donaldson Jasmine J   Binda Caroline S CS   Powell Sophie S   Chughtai Uroosa U   Edwards Gareth G   Stone Joseph J   Lobanov Sergey S   Elliston Linda L   Schuhmacher Laura-Nadine LN   Rees Elliott E   Menzies Georgina G   Ciosi Marc M   Maxwell Alastair A   Chao Michael J MJ   Hong Eun Pyo EP   Lucente Diane D   Wheeler Vanessa V   Lee Jong-Min JM   MacDonald Marcy E ME   Long Jeffrey D JD   Aylward Elizabeth H EH   Landwehrmeyer G Bernhard GB   Rosser Anne E AE   Paulsen Jane S JS   Williams Nigel M NM   Gusella James F JF   Monckton Darren G DG   Allen Nicholas D ND   Holmans Peter P   Jones Lesley L   Massey Thomas H TH  

Nature neuroscience 20220404 4


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 clust  ...[more]

Similar Datasets

| S-EPMC7160095 | biostudies-literature
| S-EPMC8424649 | biostudies-literature
| S-EPMC6360275 | biostudies-literature
| S-EPMC7645713 | biostudies-literature
| S-EPMC7990448 | biostudies-literature
| S-EPMC2714728 | biostudies-literature
| S-EPMC6700281 | biostudies-literature
| S-EPMC7990447 | biostudies-literature
| S-EPMC3000365 | biostudies-literature
| S-EPMC5550581 | biostudies-other