Generation of human induced pluripotent stem cell lines from patients with FGFR2-linked syndromic craniosynostosis.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-10-01 Epub Date: 2025-09-18 DOI:10.1242/dmm.052123
Max Gijsbertsen, Irene M J Mathijssen, Ana F Duarte Madancos, Johannes P T M van Leeuwen, Jeroen van de Peppel
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引用次数: 0

Abstract

Craniosynostosis is a multigenic congenital condition in which one or more calvarial sutures have prematurely fused during the development of the fetus. Pathogenic variants in FGFR2 are associated with the development of syndromic craniosynostosis, such as Crouzon, Apert and Pfeifer syndromes. Investigation of FGFR2-linked craniosynostosis is hindered by the lack of appropriate in vitro models. Patient-derived human induced pluripotent stem cell (hiPSC) in vitro disease models provide the opportunity to investigate the disease, identify molecular targets for pharmaceutical treatments, and enable the generation of autologous pluripotent stem cell catalogues. Here, we report three patient-derived hiPSC lines carrying the C342Y, S252W or E565G FGFR2 pathogenic variant. The patient hiPSC lines express characteristic pluripotency markers and display distinct phosphorylation profiles under unstimulated conditions. FGFR2C342Y showed autophosphorylation in the absence of bFGF ligand, although downstream docking proteins PLCγ and FRS2α were not phosphorylated. FGFR2S252W and FGFR2E565G hiPSCs showed increased phosphorylation of docking proteins PLCγ and FRS2α, whereas FGFR2 was not phosphorylated. These patient hiPSC lines provide molecular and cellular options to investigate FGFR2-linked craniosynostosis in the patient-specific genomic context and develop therapeutic modalities.

来自fgfr2相关综合征颅缝闭闭患者的三种人类诱导多能干细胞系的产生
颅缝闭锁是一种多基因先天性疾病,在胎儿发育过程中,一个或多个颅缝过早融合。FGFR2突变与综合征性颅缝闭闭的发生有关,如Crouzon、Apert和Pfeifer综合征。由于缺乏合适的体外模型,fgfr2相关颅缝闭锁的研究受到阻碍。患者来源的人诱导多能干细胞(hiPSC)体外疾病模型为研究疾病、确定药物治疗的分子靶点以及生成自体多能干细胞目录提供了机会。在这里,我们报告了三个患者来源的携带FGFR2突变C342Y, S252W或E565G的hiPSC系。患者的hiPSC系表达特征性的多能性标记,并在非刺激条件下显示出不同的磷酸化谱。在缺乏bFGF配体的情况下,FGFR2C342Y表现出自磷酸化,尽管下游对接蛋白PLCγ和FRS2α没有磷酸化。FGFR2S252W和FGFR2E565G hiPSCs的对接蛋白PLCγ和FRS2α磷酸化增加,而FGFR2不磷酸化。这些患者hiPSC细胞系为研究fgfr2相关颅缝闭锁在患者特异性基因组背景下的分子和细胞选择提供了选择,并制定了治疗方案。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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