RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.

Autor:	Benkirane M; Department of Molecular Genetics, Institut Universitaire de Recherche Clinique (IURC), Montpellier Hospital, Montpellier, France.; Genetics and Pathophysiology of NeuroMuscular Disorders, PhyMedExp Research Unit, CNRS, INSERM, University of Montpellier, Montpellier, France., Da Cunha D; Genetics and Pathophysiology of NeuroMuscular Disorders, PhyMedExp Research Unit, CNRS, INSERM, University of Montpellier, Montpellier, France., Marelli C; Department of Neurology, Montpellier Hospital, Montpellier, France.; Molecular Mechanisms of Neurodegenerative Dementia (MMDN), EPHE University of Montpellier, INSERM, Montpellier, France., Larrieu L; Department of Molecular Genetics, Institut Universitaire de Recherche Clinique (IURC), Montpellier Hospital, Montpellier, France., Renaud M; Department of Medical Genetics, Nancy Hospital, Nancy, France., Varilh J; Genetics and Pathophysiology of NeuroMuscular Disorders, PhyMedExp Research Unit, CNRS, INSERM, University of Montpellier, Montpellier, France., Pointaux M; Department of Molecular Genetics, Institut Universitaire de Recherche Clinique (IURC), Montpellier Hospital, Montpellier, France., Baux D; Department of Molecular Genetics, Institut Universitaire de Recherche Clinique (IURC), Montpellier Hospital, Montpellier, France., Ardouin O; Department of Molecular Genetics, Institut Universitaire de Recherche Clinique (IURC), Montpellier Hospital, Montpellier, France., Vangoethem C; Department of Molecular Genetics, Institut Universitaire de Recherche Clinique (IURC), Montpellier Hospital, Montpellier, France., Taulan M; Genetics and Pathophysiology of NeuroMuscular Disorders, PhyMedExp Research Unit, CNRS, INSERM, University of Montpellier, Montpellier, France., Daumas Duport B; Department of Radiology, Nantes Hospital, Nantes, France., Bergougnoux A; Department of Molecular Genetics, Institut Universitaire de Recherche Clinique (IURC), Montpellier Hospital, Montpellier, France.; Genetics and Pathophysiology of NeuroMuscular Disorders, PhyMedExp Research Unit, CNRS, INSERM, University of Montpellier, Montpellier, France., Corbillé AG; Department of Neurology, Nantes Hospital, Nantes, France., Cossée M; Department of Molecular Genetics, Institut Universitaire de Recherche Clinique (IURC), Montpellier Hospital, Montpellier, France.; Genetics and Pathophysiology of NeuroMuscular Disorders, PhyMedExp Research Unit, CNRS, INSERM, University of Montpellier, Montpellier, France., Juntas Morales R; Department of Neurology, Montpellier Hospital, Montpellier, France., Tuffery-Giraud S; Genetics and Pathophysiology of NeuroMuscular Disorders, PhyMedExp Research Unit, CNRS, INSERM, University of Montpellier, Montpellier, France., Koenig M; Department of Molecular Genetics, Institut Universitaire de Recherche Clinique (IURC), Montpellier Hospital, Montpellier, France.; Genetics and Pathophysiology of NeuroMuscular Disorders, PhyMedExp Research Unit, CNRS, INSERM, University of Montpellier, Montpellier, France., Isidor B; Department of Medical Genetics, Nantes Hospital, Nantes, France., Vincent MC; Department of Molecular Genetics, Institut Universitaire de Recherche Clinique (IURC), Montpellier Hospital, Montpellier, France.; Genetics and Pathophysiology of NeuroMuscular Disorders, PhyMedExp Research Unit, CNRS, INSERM, University of Montpellier, Montpellier, France.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2022 Nov 21; Vol. 145 (11), pp. 3770-3775.
DOI:	10.1093/brain/awac280
Abstrakt:	Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited late-onset neurological disease caused by bi-allelic AAGGG pentanucleotide expansions within intron 2 of RFC1. Despite extensive studies, the pathophysiological mechanism of these intronic expansions remains elusive. We screened by clinical exome sequencing two unrelated patients presenting with late-onset ataxia. A repeat-primer polymerase chain reaction was used for RFC1 AAGGG intronic expansion identification. RFC1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction. We identified the first two CANVAS affected patients who are compound heterozygous for RFC1 truncating variants (p.Arg388* and c.575delA, respectively) and a pathological AAGGG expansion. RFC1 expression studies in whole blood showed a significant reduction of RFC1 mRNA for both patients compared to three patients with bi-allelic RFC1 expansions. In conclusion, this observation provides clues that suggest bi-allelic RFC1 conditional loss-of-function as the cause of the disease. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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