Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency

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• 作者：Yuki Tsujita ; MD^a ; ^&lowast ; ; Kanako Mitsui-Sekinaka ; MD^a ; ^&lowast ; ; Kohsuke Imai ; MD ; PhD^a ; ^b ; ^{kimai.ped@tmd.ac.jp} ; Tzu-Wen Yeh ; MSc^c ; Noriko Mitsuiki ; MD ; PhD^c ; Takaki Asano ; MD^d ; Hidenori Ohnishi ; MD ; PhD^e ; Zenichiro Kato ; MD ; PhD^e ; ^f ; Yujin Sekinaka ; MD^a ; Kiyotaka Zaha ; MD^a ; Tamaki Kato ; MD ; PhD^a ; Tsubasa Okano ; MD^c ; Takehiro Takashima ; MD^c ; Kaoru Kobayashi ; MD ; PhD^g ; Mitsuaki Kimura ; MD ; PhD^h ; Tomoaki Kunitsu ; MDⁱ ; Yoshihiro Maruo ; MD ; PhDⁱ ; Hirokazu Kanegane ; MD ; PhD^c ; Masatoshi Takagi ; MD ; PhD^c ; Kenichi Yoshida ; MD ; PhD^j ; Yusuke Okuno ; MD ; PhD^k ; Hideki Muramatsu ; MD ; PhD^k ; Yuichi Shiraishi ; PhD^l ; Kenichi Chiba ; BA^l ; Hiroko Tanaka ; BSc^m ; Satoru Miyano ; PhD^l ; ^m ; Seiji Kojima ; MD ; PhD^k ; Seishi Ogawa ; MD ; PhD^j ; Osamu Ohara ; PhDⁿ ; Satoshi Okada ; MD ; PhD^d ; Masao Kobayashi ; MD ; PhD^d ; Tomohiro Morio ; MD ; PhD^c ; Shigeaki Nonoyama ; MD ; PhD^a
• 关键词：Activated phosphatidylinositol 3-kinase δ syndrome ; catalytic subunit p110δ of phosphatidylinositol 3-kinase ; phosphatase and tensin homolog ; primary immunodeficiency disease
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：138
• 期：6
• 页码：1672-1680.e10
• 全文大小：4068 K
• 卷排序：138

文摘

Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6.ObjectiveThis study aimed to identify novel genes responsible for APDS.MethodsWhole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays.ResultsWe identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway.ConclusionPTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.