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Novel In-Frame Deletion Mutation in NOTCH1 in a Chinese Sporadic Case of Adams-Oliver Syndrome.

Adams-Oliver综合征中国散发性病例NOTCH1 新的框内缺失突变。

  • 影响因子:2.78
  • DOI:10.1089/dna.2019.5200
  • 作者列表:"Huang S","Yang L","Zhao L","Xu R","Wu Y
  • 发表时间:2020-05-01
Abstract

:Adams-Oliver syndrome (AOS) is a rare hereditary disorder characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects. The etiology of AOS has remained largely unknown, although mutations in the notch receptor 1 (NOTCH1) gene are most common genetic alteration associated with this disease. In this study, we aimed to identify the case of a 6-year-old boy, who presented with large ACC of the scalp and aortic valve stenosis, suggesting the possibility of AOS. Whole-exome sequencing identified a novel, de novo, in-frame deletion in the NOTCH1 gene (NOTCH1 c.1292_1294del, p.Asn431del) in the patient. The p.Asn431del variant was evaluated by several in silico analyses, which predicted that the mutant was likely to be pathogenic. In addition, molecular modeling with the PyMOL Molecular Graphics System suggested that the NOTCH1-N431del destabilizes calcium ion chelation, leading to decreased receptor-ligand binding efficiency. Quantitative reverse transcription PCR showed further significant downregulation of the Notch target genes, hes-related family bHLH transcription factor with YRPW motif 1 (HEY1) and hes family bHLH transcription factor 1 (HES1), suggesting that this mutation causes disease through dysregulation of the Notch signaling pathway. Our study provides evidence that the NOTCH1-N431del mutation is responsible for this case of AOS. To our knowledge, this is the first report of a patient with AOS caused by NOTCH1 mutation in Asia, and this information will be useful for providing the family with genetic counseling that can help to guide their future plans.

摘要

: Adams-Oliver综合征 (AOS) 是一种罕见的遗传性疾病,以先天性皮肤发育不全 (ACC) 和终末横肢缺损为特征。AOS的病因在很大程度上仍然未知,尽管notch受体 1 (NOTCH 1) 基因的突变是与该疾病相关的最常见的遗传改变。在这项研究中,我们旨在确定一例 6 岁男孩,表现为头皮和主动脉瓣狭窄的大ACC,提示AOS的可能性。全外显子组测序鉴定了患者NOTCH1 基因 (NOTCH1 c.1292 _ 1294del,p.Asn431del) 中一个新的、从头开始的框内缺失。P.Asn431del变异体通过几个计算机分析进行评价,预测该突变体可能是致病性的。此外,PyMOL分子图形系统的分子建模表明,NOTCH1-N431del不稳定钙离子螯合,导致受体-配体结合效率降低。定量逆转录PCR显示Notch靶基因进一步显著下调,hes相关家族bHLH转录因子与YRPW基序 1 (HEY 1) 和hes家族bHLH转录因子 1 (HES 1),提示该突变通过Notch信号通路的失调引起疾病。我们的研究提供了NOTCH1-N431del突变导致AOS的证据。据我们所知,这是亚洲首次报道NOTCH1 突变导致AOS患者,这些信息将有助于为家庭提供遗传咨询,帮助指导他们未来的计划。

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影响因子:0.95
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影响因子:2.43
发表时间:2020-01-15
DOI:10.5435/JAAOS-D-16-00918
作者列表:["Grigoryan G","Korcek L","Eidelman M","Paley D","Nelson S"]

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