生物
共济失调
遗传学
移码突变
聚合酶链反应
小脑共济失调
外显子
基因
神经科学
作者
Mehdi Benkirane,Dylan Da Cunha,Cecilia Marelli,Lise Larrieu,Mathilde Renaud,Jessica Varilh,Morgane Pointaux,David Baux,Olivier Ardouin,C. VanGoethem,Magali Taulan,Benjamin Daumas Duport,Anne Bergougnoux,Anne-Gaëlle Corbillé,Mireille Cossée,Raúl G. E. Morales,Sylvie Tuffery-Giraud,M. Koenig,Bertrand Isidor,Marie-Claire Vincent
出处
期刊:Brain
[Oxford University Press]
日期:2022-07-27
卷期号:145 (11): 3770-3775
被引量:2
标识
DOI:10.1093/brain/awac280
摘要
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.
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