Functional characterization of variants of unknown significance in a spinocerebellar ataxia patient using an unsupervised machine learning pipeline.
Journal
Human genome variation
ISSN: 2054-345X
Titre abrégé: Hum Genome Var
Pays: England
ID NLM: 101652445
Informations de publication
Date de publication:
14 Apr 2022
14 Apr 2022
Historique:
received:
23
07
2021
accepted:
23
02
2022
revised:
08
02
2022
entrez:
15
4
2022
pubmed:
16
4
2022
medline:
16
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35422034
doi: 10.1038/s41439-022-00188-8
pii: 10.1038/s41439-022-00188-8
pmc: PMC9010413
doi:
Types de publication
Journal Article
Langues
eng
Pagination
10Subventions
Organisme : Krembil Foundation
ID : kf001
Organisme : Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre)
ID : PJT153063
Informations de copyright
© 2022. The Author(s).
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