具有 PTEN 种系突变的个体接受 PTEN 错构瘤肿瘤综合征 (PHTS) 的分子诊断。 PHTS 显示出一系列复杂的临床表型，包括错构瘤、癌症倾向和自闭症谱系障碍 (ASD)。由于有关 PTEN 功能受突变影响的信息不足，尚未建立明确的基因型-表型相关性。为了填补这一知识空白，我们使用基因编辑的人类诱导多能干细胞 (hiPSC) 比较了两个选定的错义 PTEN 突变等位基因 G132D 和 M134R 的功能影响，每个基因分别与不同的临床表型、ASD 或无 ASD 的甲状腺癌相关。在纯合 hiPSC 中，由于蛋白质半衰期缩短，M134R 突变导致 PTEN 表达严重降低。 G132D 抑制 PTEN 表达的程度低于 M134R 突变，且不改变蛋白质半衰期。当受到 γ 射线照射时，G132D 杂合细胞比野生型和 M134R 杂合 hiPSC 更早退出辐射诱导的 G2 停滞，尽管 DNA 损伤水平与后两者相似。免疫印迹分析表明，γ 辐射诱导 G132D 杂合细胞凋亡的程度低于其他基因型的 hiPSC。这些数据表明，ASD 相关的 G132D 等位基因通过过早的细胞周期重入和不完整的 DNA 修复来促进基因组不稳定。© 2023。作者，获得 Springer Nature Limited 的独家许可。

Individuals with a PTEN germline mutation receive the molecular diagnosis of PTEN hamartoma tumor syndrome (PHTS). PHTS displays a complex spectrum of clinical phenotypes including harmartomas, predisposition to cancers, and autism spectrum disorder (ASD). Clear-cut genotype-phenotype correlations are yet to be established due to insufficient information on the PTEN function being impacted by mutations. To fill this knowledge gap, we compared functional impacts of two selected missense PTEN mutant alleles, G132D and M134R, each respectively being associated with distinct clinical phenotype, ASD or thyroid cancer without ASD using gene-edited human induced pluripotent stem cells (hiPSCs). In homozygous hiPSCs, PTEN expression was severely reduced by M134R mutation due to shortened protein half-life. G132D suppressed PTEN expression to a lesser extent than Μ134R mutation without altering protein half-life. When challenged with γ-irradiation, G132D heterozygous cells exited radiation-induced G2 arrest earlier than wildtype and M134R heterozygous hiPSCs despite the similar DNA damage levels as the latter two. Immunoblotting analyses suggested that γ-irradiation induced apoptosis in G132D heterozygous cells to lesser degrees than in the hiPSCs of other genotypes. These data suggest that ASD-associated G132D allele promotes genome instability by premature cell cycle reentry with incomplete DNA repair.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.