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An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.

VWA1中祖先10 bp重复扩增导致隐性遗传性运动神经病。

  • 影响因子:0
  • DOI:10.1093/brain/awaa420
  • 作者列表:"Pagnamenta AT","Kaiyrzhanov R","Zou Y","Da'as SI","Maroofian R","Donkervoort S","Dominik N","Lauffer M","Ferla MP","Orioli A","Giess A","Tucci A","Beetz C","Sedghi M","Ansari B","Barresi R","Basiri K","Cortese A","Elgar G","Fernandez-Garcia MA","Yip J","Foley AR","Gutowski N","Jungbluth H","Lassche S","Lavin T","Marcelis C","Marks P","Marini-Bettolo C","Medne L","Moslemi AR","Sarkozy A","Reilly MM","Muntoni F","Millan F","Muraresku CC","Need AC","Nemeth AH","Neuhaus SB","Norwood F","O'Donnell M","O'Driscoll M","Rankin J","Yum SW","Zolkipli-Cunningham Z","Brusius I","Wunderlich G","Genomics England Research Consortium.","Karakaya M","Wirth B","Fakhro KA","Tajsharghi H","Bönnemann CG","Taylor JC","Houlden H
  • 发表时间:2021-03-03
Abstract

:The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.

摘要

: 细胞外基质包含大分子如胶原蛋白、蛋白聚糖和糖蛋白的网络。VWA1 (含有1的血管性血友病因子A结构域) 编码与perlecan/collagen VI相互作用的细胞外基质组分,似乎参与稳定细胞外基质结构,并在胫神经中表现出高表达水平。Vwa1-deficient小鼠表现出异常的外周神经结构/功能; 然而,VWA1变体以前与人类疾病无关。通过询问来自180 K基因组计划的74   100个体的基因组序列,结合国际基因匹配努力和靶向测序,我们从15个家系中鉴定了17个具有常染色体隐性遗传、非长度依赖性、遗传性运动神经病和vwa1中罕见双等位基因变异的个体。在14/15个家族中观察到单个疾病相关等位基因p.(G25Rfs * 74),10-bp重复扩增,并且在10/15个家族中是纯合的。鉴于欧洲人群中的等位基因频率接近1/1000,从100K基因组计划中确定的7个不相关纯合子个体代表了高于预期的实质性富集。单体型分析鉴定了一个共享的220 kb区域,表明这个创始人突变出现在> 7000年前。宽年龄范围的患者 (6-83岁) 有助于随着时间的推移描绘临床表型。队列中最常见的疾病表现是早发性 (平均2.0 ± 1.4岁) 非长度依赖性轴突遗传性运动神经病,经电生理学证实,必须与其他主要或纯运动神经病和神经病鉴别。由于疾病进展缓慢,行走在很大程度上得以保持。神经生理学、肌肉组织病理学和肌肉MRI表现通常显示明显的神经源性改变,单个孤立病例显示额外的肌病过程。我们推测,肌病改变的一些发现可能继发于慢性失神经支配,而不是指示额外的肌病过程。使用患者成纤维细胞的双重逆转录聚合酶链反应和免疫印迹揭示,创始人等位基因导致部分无义介导的衰变和可检测蛋白的缺失。斑马鱼中的CRISPR和morpholino vwa1建模证明运动神经元轴突生长、骨骼肌突触形成和机车行为减少。总之,我们估计VWA1中的双等位基因变异可能导致欧洲人高达1% 的不明原因遗传性运动神经病病例。本文提供的详细临床表征将有助于对合适的患者队列进行靶向测试。由于高GC含量、随之而来的低覆盖度和与稳健检测重复扩增相关的计算困难,这种新的疾病基因可能先前已经逃避检测。使用较低QC过滤器审查先前未解决的外显子组可能会产生进一步的诊断。

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