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与免疫缺陷相关的激活PIK3R1变体的矛盾的主导负面活性
Patsy R Tomlinson1,2, Rachel Knox1,2,3, Olga Perisic4
1The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
bioRxiv : the preprint server for biology
|December 11, 2023
概括
宪法PIK3R1突变导致SHORT综合征或APDS2. 激活PIK3R1 (APDS2) 中的突变矛盾地导致p110α的低功能,解释了组合的功能获取和功能丧失表型.
科学领域:
- 遗传学和分子生物学
- 内分泌学 在内分泌学.
- 免疫学 免疫学 免疫学
背景情况:
- 基因PIK3R1编码了IA类酸酸酶3-激酶 (PI3K) 的调控子单元.
- 宪法PIK3R1突变导致不同的表型:功能丧失突变导致SHORT综合征 (胰岛素抵抗,矮身),而激活突变导致APDS2 (免疫缺陷).
- 一个令人费解的观察是,尽管APDS2患者激活了突变,但他们经常表现出类似SHORT综合征的特征,这表明同时存在p110α低功能的情况.
研究的目的:
- 调查功能增加和功能丧失PIK3R1表型同时发生背后的机制.
- 了解如何激活PIK3R1突变可能导致减少p110α功能.
主要方法:
- 来自APDS2患者皮肤纤维细胞的分析.
- 对PI3K信号通路的评估.
- 对p110δ表达水平的研究.
- 在前脂肪细胞中研究PIK3R1变体与Irs1和Irs2的相互作用.
- 检查PIK3R1变体和p110α之间的异构化.
主要成果:
- 来自APDS2患者的皮肤纤维细胞没有显示PI3K信号的增加,并且明显减少了p110δ表达.
- APDS2变种在前脂肪细胞中表现出强大的主导负效应.
- APDS2变种与Irs1和Irs2相关,但未能与p110α异构.
- 这种相互作用减弱了p110α信号传输.
结论:
- 激活PIK3R1突变 (APDS2) 可以对p110α产生主导负面影响,导致其功能下降.
- APDS2变体的这种主导负活性解释了功能增益 (免疫缺陷) 和功能丧失 (SHORT综合征样特征) 现象型的同时发生.
- 与PIK3R1相关疾病的基因型-表型关系比最初理解的要复杂得多,涉及复杂的调节机制.
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