A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects.,Clinical Genetics

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A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects.
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-03-17 , DOI: 10.1111/cge.13742
Eun Hye Cho ₁ , Hee Jae Huh ₁ , Inyoung Jeong ₂ , Nam Yong Lee ₁ , Won-Jung Koh ₃ , Hae-Chul Park ₂ , Chang-Seok Ki ₄

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Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by defects in the function or structure of motitle cilia. In most cases, causative variants result in axonemal dynein arm anomalies, however, PCD due to radial spoke (RS) and central pair (CP) of microtubules has been rarely reported. To identify the molecular basis of PCD characterized by RS/CP defects, we performed whole exome sequencing in PCD patients with RS/CP defects. We identified a homozygous nonsense variant (c.572G>A; p.Trp191*) in NME5 , which encodes a protein component of the RS neck, in one PCD patient with situs solitus . Morpholino knockdown of nme5 in zebrafish embryos resulted in motile cilia defects with phenotypes compatible with ciliopathy. This is the first study to show NME5 as a PCD‐causative gene in humans. Our findings indicate that NME5 screening should be considered for PCD patients with RS/CP defects.

中文翻译：

NME5中无意义的变异会导致人类原发性睫状运动障碍，并伴有放射状辐条缺陷。

原发性睫状运动障碍（PCD）是一种遗传异质性疾病，其特征是原状纤毛的功能或结构缺陷。在大多数情况下，致病性变异会导致轴突动力臂异常，但是，因微管的径向辐条（RS）和中央对（CP）而引起的PCD很少见。为了确定以RS / CP缺陷为特征的PCD的分子基础，我们对患有RS / CP缺陷的PCD患者进行了全外显子组测序。我们确定了纯合的无义变体（c.572G> A; p.Trp191 *）在NME5，其编码RS颈部的蛋白质成分，与一种PCD患者正位。nme5的Morpholino抑制在斑马鱼的胚胎中导致活动性纤毛缺陷，其表型与纤毛病相容。这是第一项显示NME5是人类PCD致病基因的研究。我们的发现表明，对于患有RS / CP缺陷的PCD患者，应考虑进行NME5筛查。

更新日期：2020-03-17

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