Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome
Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome
复制标题
DOI：
10.1093/brain/awab363
复制
发表时间：
2022-03-29
期刊：
影响因子：
14.5
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
--
作者：
Miyatake, Satoko;Yoshida, Kunihiro;Matsumoto, Naomichi
小脑共济失调、神经病、前庭反射消失综合征（CANVAS）是一种迟发性、进展缓慢的多系统神经退行性疾病。RFC 1中的双等位基因AAGGG重复扩增已被确定为这种疾病的病因，最近还暗示了重复构象异质性（ACAGG重复）。为了对日本成人型共济失调患者的这种疾病进行分子特征分析，我们通过侧翼PCR、重复引物PCR、Southern印迹和使用Sequel II、GridION或PromethION的长读序测序组成的综合方法，积累并筛选了212个候选家族。我们确定了来自11个家族的16例患者，其中7例具有ACAGG扩增[（ACAGG）（exp）/（ACAGG）（exp）]（ACAGG纯合子），2例具有ACAGG和AAGGG扩增[（ACAGG）（exp）/（AAGGG）（exp）]（ACAGG/AAGGG复合杂合子），7例具有AAGGG扩增[（AAGGG）（exp）/（AAGGG）（exp）]（AAGGG纯合子）。总检出率为5.2%（11/212个家庭，包括一个家庭有两个扩展基因型）。长读段测序仪在核苷酸分辨率水平上显示了AAGGG和ACAGG重复扩增的整个序列。临床评估和神经病理学结果表明，ACAGG扩增患者与先前报道的纯合子AAGGG扩增患者具有相似的临床特征，尽管运动神经元受累在ACAGG扩增患者中更明显（即使涉及一个等位基因）。此外，在我们非常有限的队列中，与ACAGG或AAGGG纯合子相比，ACAGG/AAGGG复合杂合子扩增患者的发病年龄晚，临床进展慢。我们的研究清楚地表明重复构象异质性的发生，对受影响的神经系统可能有不同的影响。也可能怀疑复合杂合子和纯合子之间疾病发作和进展的差异，但由于我们研究的病例样本量小，确定性非常有限。需要对更多患者进行研究以证实这一点。
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)(exp)/(ACAGG)(exp)] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)(exp)/(AAGGG)(exp)] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)(exp)/(AAGGG)(exp)] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.