%0 Journal Article
%T RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.
%A Benkirane M
%A Da Cunha D
%A Marelli C
%A Larrieu L
%A Renaud M
%A Varilh J
%A Pointaux M
%A Baux D
%A Ardouin O
%A Vangoethem C
%A Taulan M
%A Daumas Duport B
%A Bergougnoux A
%A Corbillé AG
%A Cossée M
%A Juntas Morales R
%A Tuffery-Giraud S
%A Koenig M
%A Isidor B
%A Vincent MC
%J Brain
%V 145
%N 11
%D 11 2022 21
%M 35883251
%F 15.255
%R 10.1093/brain/awac280
%X 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.