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首页> 外文期刊>European journal of human genetics: EJHG >A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway
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A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway

机译:一种新的主导阴性FGFR1变体通过放松RAS / ERK1 / 2通路导致HARTSFIELD综合征

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摘要

Hartsfield syndrome (HS) is an ultrarare developmental disorder mainly featuring holoprosencephaly and ectrodactyly. It is caused by heterozygous or biallelic variants in FGFR1. Recently, a dominant-negative effect was suggested for FGFR1 variants associated with HS. Here, exome sequencing analysis in a 12-year-old boy with HS disclosed a novel de novo heterozygous variant c.1934C>T in FGFR1 predicted to cause the p.(Ala645Val) amino-acid substitution. In order to evaluate whether the variant, changing a highly conserved residue of the kinase domain, affects FGFR1 function, biochemical studies were employed. We measured the FGFR1 receptor activity in FGF2-treated cell lines exogenously expressing wild-type or Ala645Val FGFR1 by monitoring the activation status of FGF2/FGFR1 downstream pathways. Our analysis highlighted that RAS/ERK1/2 signaling was significantly perturbed in cells expressing mutated FGFR1, in comparison with control cells. We also provided preliminary evidence showing a modulation of the autophagic process in cells expressing mutated FGFR1. This study expands the FGFR1 mutational spectrum associated with HS, provides functional evidence further supporting a dominant-negative effect of this category of FGFR1 variants and offers initial insights on dysregulation of autophagy in HS.
机译:HARTSFIELD综合征(HS)是超空地发育障碍,主要具有全华症和重新切除。它是由FGFR1中的杂合或双腿变体引起的。最近,提出了与HS相关的FGFR1变体的显性负面影响。这里,在HS的12岁男孩中exome测序分析公开了一种在预测的FGFR1中的新型Novo杂合子变体C.1934C> T.(ALA645VAL)氨基酸取代。为了评估是否改变激酶结构域的高度保守残余物的变体影响FGFR1功能,采用生化研究。通过监测FGF2 / FGFR1下游途径的激活状态,在外源表达野生型或ALA645VAL FGFR1的FGF2处理细胞系中的FGFR1受体活性。与对照细胞相比,我们的分析突出显示RAS / ERK1 / 2信号在表达FGFR1的细胞中显着扰乱。我们还提供了初步证据,显示表达突变FGFR1的细胞中的自噬过程的调节。本研究扩展了与HS相关的FGFR1突变谱,提供了功能的功能证据,进一步支持这类FGFR1变体的主要负效应,并对HS中自噬的失调提供了初步见解。

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    Fdn IRCCS Casa Sollievo della Sofferenza Div Med Genet San Giovanni Rotondo FG Italy;

    Fdn IRCCS Casa Sollievo della Sofferenza Div Med Genet San Giovanni Rotondo FG Italy;

    Univ Milan Studi Milano Dept Pharmacol &

    Biomol Sci Milan Italy;

    Fdn IRCCS Casa Sollievo della Sofferenza Unit Bioinformat San Giovanni Rotondo FG Italy;

    Fdn IRCCS Casa Sollievo della Sofferenza Div Med Genet San Giovanni Rotondo FG Italy;

    Fdn IRCCS Casa Sollievo della Sofferenza Div Pediat San Giovanni Rotondo FG Italy;

    Natl Res Council CNR Inst Biosci &

    Bioresources Naples Italy;

    Fdn IRCCS Casa Sollievo della Sofferenza Div Med Genet San Giovanni Rotondo FG Italy;

    Fdn IRCCS Casa Sollievo della Sofferenza Div Med Genet San Giovanni Rotondo FG Italy;

    Fdn IRCCS Casa Sollievo della Sofferenza Div Med Genet San Giovanni Rotondo FG Italy;

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  • 正文语种 eng
  • 中图分类 医学遗传学;
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