RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.
Brain
; 145(11): 3770-3775, 2022 11 21.
Article
en En
| MEDLINE
| ID: mdl-35883251
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ataxia Cerebelosa
/
Enfermedades del Sistema Nervioso Periférico
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Proteína de Replicación C
/
Vestibulopatía Bilateral
Límite:
Humans
Idioma:
En
Revista:
Brain
Año:
2022
Tipo del documento:
Article
País de afiliación:
Francia