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5' UTR CGG repeat expansion in GIPC1 is associated with oculopharyngodistal myopathy.

GIPC1中的5 'UTR CGG重复扩增与眼咽部远端肌病相关。

  • 影响因子:0
  • DOI:10.1093/brain/awaa426
  • 作者列表:"Xi J","Wang X","Yue D","Dou T","Wu Q","Lu J","Liu Y","Yu W","Qiao K","Lin J","Luo S","Li J","Du A","Dong J","Chen Y","Luo L","Yang J","Niu Z","Liang Z","Zhao C","Lu J","Zhu W","Zhou Y
  • 发表时间:2021-03-03
Abstract

:Oculopharyngodistal myopathy is a late-onset degenerative muscle disorder characterized by ptosis and weakness of the facial, pharyngeal, and distal limb muscles. A recent report suggested a non-coding trinucleotide repeat expansion in LRP12 to be associated with the disease. Here we report a genetic study in a Chinese cohort of 41 patients with the clinical diagnosis of oculopharyngodistal myopathy (21 cases from seven families and 20 sporadic cases). In a large family with 12 affected individuals, combined haplotype and linkage analysis revealed a maximum two-point logarithm of the odds (LOD) score of 3.3 in chromosomal region chr19p13.11-p13.2 and narrowed the candidate region to an interval of 4.5 Mb. Using a comprehensive strategy combining whole-exome sequencing, long-read sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal CGG repeat expansion in the 5' UTR of the GIPC1 gene that co-segregated with disease. Overall, the repeat expansion in GIPC1 was identified in 51.9% independent pedigrees (4/7 families and 10/20 sporadic cases), while the repeat expansion in LRP12 was only identified in one sporadic case (3.7%) in our cohort. The number of CGG repeats was <30 in controls but >60 in affected individuals. There was a slight correlation between repeat size and the age at onset. Both repeat expansion and retraction were observed during transmission but somatic instability was not evident. These results further support that non-coding CGG repeat expansion plays an essential role in the pathogenesis of oculopharyngodistal myopathy.

摘要

: 眼咽下肌远端肌病是一种晚发性退行性肌肉疾病,其特征是上睑下垂和面部、咽部和肢体远端肌肉无力。最近的报道表明LRP12中的非编码三核苷酸重复扩增与该疾病相关。在这里,我们报告了一项在41例临床诊断为眼咽下远端肌病的中国队列中的遗传学研究 (来自7个家庭的21例和20例散发性病例)。在一个有12个患病个体的大家族中,结合单倍型和连锁分析,在染色体区域chr19p13.11-p13.2中,赔率 (LOD) 得分的最大两点对数为3.3,并将候选区域缩小到4.5 Mb的区间。采用全外显子组测序、长读测序、重复引物聚合酶链反应和富含GC的聚合酶链反应相结合的综合策略,我们在与疾病共分离的GIPC1基因的5 'UTR中发现了异常的CGG重复扩增。总体而言,在51.9% 个独立家系 (4/7个家庭和10/20例散发病例) 中发现了GIPC1的重复扩增,而在我们的队列中,LRP12的重复扩增仅在1例散发病例 (3.7%) 中发现。CGG重复的数目在对照中 <30,但在受影响的个体中> 60。重复大小与发病年龄之间存在轻微的相关性。在传播期间观察到重复扩增和回缩,但体细胞不稳定性不明显。这些结果进一步支持非编码CGG重复扩增在眼咽部远端肌病的发病机制中起重要作用。

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