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首页> 外文期刊>Human mutation >TAB2 TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis
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TAB2 TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis

机译：Tab2 Tab2 C.1398Dup变体导致臭氧水能和损害细胞外基质稳态

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摘要

Abstract Transforming growth factor β‐activated kinase 1 (TAK1) mediates multiple biological processes through the nuclear factor κ‐light‐chain‐enhancer of activated B cells (NF‐κB) and the mitogen‐activated protein kinase (MAPK) signaling pathways. TAK1 activation is tightly regulated by its binding partners (TABs). In particular, binding with TAB2 is crucial for cardiovascular development and extracellular matrix (ECM) homeostasis. In our previous work, we reported a novel multisystem disorder associated with the heterozygous TAB2 c.1398dup variant. Here, we dissect the functional effects of this variant in order to understand its molecular pathogenesis. We demonstrate that TAB2 c.1398dup considerably undergoes to nonsense‐mediated messenger RNA decay and encodes a truncated protein that loses its ability to bind TAK1. We also show an alteration of the TAK1 autophosphorylation status and of selected downstream signaling pathways in patients’ fibroblasts. Immunofluorescence analyses and ECM‐related polymerase chain reaction‐array panels highlight that patient fibroblasts display ECM disorganization and altered expression of selected ECM components and collagen‐related pathways. In conclusion, we deeply dissect the molecular pathogenesis of the TAB2 c.1398dup variant and show that the resulting phenotype is well explained by TAB2 loss‐of‐function. Our data also offer initial insights on the ECM homeostasis impairment as a molecular mechanism probably underlying a multisystem disorder linked to TAB2 .
机译：摘要转化生长因子β-活性激酶1（TAK1）通过活化B细胞（NF-κB）的核因子κ-轻链增强剂和丝裂原活化蛋白激酶（MAPK）信号传导途径介导多种生物学过程。 TAK1激活由其绑定伙伴（标签）紧密调节。特别地，与Tab2的结合对于心血管发育和细胞外基质（ECM）稳态是至关重要的。在我们以前的工作中，我们报告了与杂合标签2 C.1398DUP变体相关的新型多系统障碍。在这里，我们描述了这种变体的功能效果以了解其分子发病机制。我们证明Tab2 C.1398Dup显着经历了非义介导的Messenger RNA衰减，并编码截短的蛋白质，这些蛋白质失去其结合Tak1的能力。我们还显示出达1型自动磷酸化状态和患者成纤维细胞中所选下游信号通路的改变。免疫荧光分析和ECM相关聚合酶链反应阵列面板突出显示患者成纤维细胞显示ECM紊乱和改变所选ECM组分和相关途径的表达。总之，我们深入描述了突片2 C.1398dup变体的分子发病机制，并表明所得表型通过舌点损失很好地解释。我们的数据还提供了对ECM Soyostasis损伤的初步见解，作为与Tab2相关的多系统障碍的分子机制。

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  • 来源
    《Human mutation》 |2019年第10期|共13页
  • 作者

    Morlino Silvia; Carbone Annalucia; Ritelli Marco; Fusco Carmela; Giambra Vincenzo; Nardella Grazia; Notarangelo Angelantonio; Panelli Patrizio; Mazzoccoli Gianluigi; Zoppi Nicoletta; Grammatico Paola; Wade Emma M; Colombi Marina; Castori Marco; Micale Lucia;

  • 作者单位

    Laboratory of Medical Genetics Department of Molecular Medicine San Camillo‐Forlanini;

    Division of Internal Medicine and Unit of ChronobiologyFondazione IRCCS Casa Sollievo della;

    Division of Biology and Genetics Department of Molecular and Translational;

    Division of Medical GeneticsFondazione IRCCS Casa Sollievo della SofferenzaFoggia Italy;

    Institute for Stem Cell Biology Regenerative Medicine and Innovative Therapies (ISBReMIT;

    Division of Medical GeneticsFondazione IRCCS Casa Sollievo della SofferenzaFoggia Italy;

    Division of Medical GeneticsFondazione IRCCS Casa Sollievo della SofferenzaFoggia Italy;

    Institute for Stem Cell Biology Regenerative Medicine and Innovative Therapies (ISBReMIT;

    Division of Internal Medicine and Unit of ChronobiologyFondazione IRCCS Casa Sollievo della;

    Division of Biology and Genetics Department of Molecular and Translational;

    Laboratory of Medical Genetics Department of Molecular Medicine San Camillo‐Forlanini;

    Department of Women's and Children's Health Dunedin School of MedicineUniversity of OtagoDunedin;

    Division of Biology and Genetics Department of Molecular and Translational;

    Division of Medical GeneticsFondazione IRCCS Casa Sollievo della SofferenzaFoggia Italy;

    Division of Medical GeneticsFondazione IRCCS Casa Sollievo della SofferenzaFoggia Italy;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 医学遗传学;
  • 关键词

    collagen; extracellular matrix; haploinsufficiency; MAPK signaling pathways; TAK1‐TAB complex;

    机译：胶原蛋白;细胞外基质;HAPLOUNSUBCY;MAPK信号传导途径;TAK1-TAB复合物;

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