Tomlinson Patsy R, Knox Rachel, Perisic Olga, Su Helen C, Brierley Gemma V, Williams Roger L, Semple Robert K
The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
bioRxiv. 2024 Nov 5:2023.11.02.565250. doi: 10.1101/2023.11.02.565250.
encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β or p110δ. Constitutional mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function phenotypes.
编码IA类磷酸肌醇3激酶（PI3K）的三个调节亚基，每个调节亚基可与三个催化亚基中的任何一个结合，即p110α、p110β或p110δ。遗传性突变会导致一些疾病，其基因型与表型的关系尚未完全阐明：杂合功能丧失性突变会导致SHORT综合征，其特征为胰岛素抵抗和身材矮小，这归因于p110α功能降低，而杂合激活突变会导致免疫缺陷，归因于p110δ激活，称为APDS2。令人惊讶的是，APDS2患者并未表现出p110α过度激活的特征，但通常确实具有类似SHORT综合征的特征，提示p110α功能减退。我们试图对此进行研究。在一名APDS2患者的皮肤成纤维细胞中，我们发现PI3K信号没有增加，而p110δ表达明显降低。在前脂肪细胞中，APDS2变体具有强大的显性负性作用，可与Irs1和Irs2结合，但无法与p110α形成异二聚体。这种由p110δ激活的PIK3R1变体对p110α信号的减弱可能解释了功能获得和功能丧失表型的同时出现。
