Functional characterization of variants of unknown significance in a spinocerebellar ataxia patient using an unsupervised machine learning pipeline.

Autor: Nath S; Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.; Department of Ophthalmology and Visual Sciences, McGill University, Montréal, QC, Canada., Caron NS; Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada., May L; Division of Neurology, Department of Medicine and Department of Pediatrics, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada., Gluscencova OB; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada., Kolesar J; Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Brady L; Genetic Counselling Program, Hamilton Health Sciences, Hamilton, ON, Canada. bradyla@hhsc.ca., Kaufman BA; Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Boulianne GL; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.; Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada., Rodriguez AR; Division of Ophthalmology, Department of Surgery, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada., Tarnopolsky MA; Division of Neurology, Department of Medicine and Department of Pediatrics, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada., Truant R; Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada. truantr@mcmaster.ca.
Jazyk: angličtina
Zdroj: Human genome variation [Hum Genome Var] 2022 Apr 14; Vol. 9 (1), pp. 10. Date of Electronic Publication: 2022 Apr 14.
DOI: 10.1038/s41439-022-00188-8
Abstrakt: CAG-expanded ATXN7 has been previously defined in the pathogenesis of spinocerebellar ataxia type 7 (SCA7), a polyglutamine expansion autosomal dominant cerebellar ataxia. Pathology in SCA7 occurs as a result of a CAG triplet repeat expansion in excess of 37 in the first exon of ATXN7, which encodes ataxin-7. SCA7 presents clinically with spinocerebellar ataxia and cone-rod dystrophy. Here, we present a novel spinocerebellar ataxia variant occurring in a patient with mutations in both ATXN7 and TOP1MT, which encodes mitochondrial topoisomerase I (top1mt). Using machine-guided, unbiased microscopy image analysis, we demonstrate alterations in ataxin-7 subcellular localization, and through high-fidelity measurements of cellular respiration, bioenergetic defects in association with top1mt mutations. We identify ataxin-7 Q35P and top1mt R111W as deleterious mutations, potentially contributing to disease states. We recapitulate our mutations through Drosophila genetic models. Our work provides important insight into the cellular biology of ataxin-7 and top1mt and offers insight into the pathogenesis of spinocerebellar ataxia applicable to multiple subtypes of the illness. Moreover, our study demonstrates an effective pipeline for the characterization of previously unreported genetic variants at the level of cell biology.
(© 2022. The Author(s).)
Databáze: MEDLINE
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