Yuki Tsujita1, Kanako Mitsui-Sekinaka1, Kohsuke Imai2, Tzu-Wen Yeh3, Noriko Mitsuiki3, Takaki Asano4, Hidenori Ohnishi5, Zenichiro Kato6, Yujin Sekinaka1, Kiyotaka Zaha1, Tamaki Kato1, Tsubasa Okano3, Takehiro Takashima3, Kaoru Kobayashi7, Mitsuaki Kimura8, Tomoaki Kunitsu9, Yoshihiro Maruo9, Hirokazu Kanegane3, Masatoshi Takagi3, Kenichi Yoshida10, Yusuke Okuno11, Hideki Muramatsu11, Yuichi Shiraishi12, Kenichi Chiba12, Hiroko Tanaka13, Satoru Miyano14, Seiji Kojima11, Seishi Ogawa10, Osamu Ohara15, Satoshi Okada4, Masao Kobayashi4, Tomohiro Morio3, Shigeaki Nonoyama1. 1. Department of Pediatrics, National Defense Medical College, Saitama, Japan. 2. Department of Pediatrics, National Defense Medical College, Saitama, Japan; Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address: kimai.ped@tmd.ac.jp. 3. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 4. Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan. 5. Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan. 6. Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan; Structural Medicine, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan. 7. Department of Surgery, Kuma Hospital, Kobe, Japan. 8. Department of Allergy and Clinical Immunology, Shizuoka Children's Hospital, Shizuoka, Japan. 9. Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan. 10. Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan. 11. Department of Pediatrics, Nagoya University Gradual School of Medicine, Nagoya, Japan. 12. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science University of Tokyo, Tokyo, Japan. 13. Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science University of Tokyo, Tokyo, Japan. 14. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science University of Tokyo, Tokyo, Japan; Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science University of Tokyo, Tokyo, Japan. 15. Department of Technology Development, Kazusa DNA Research Institute, Chiba, Japan.
Abstract
BACKGROUND: 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. OBJECTIVE: This study aimed to identify novel genes responsible for APDS. METHODS: Whole-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. RESULTS: We 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. CONCLUSION: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes. Copyright Â
BACKGROUND: 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. OBJECTIVE: This study aimed to identify novel genes responsible for APDS. METHODS: Whole-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. RESULTS: We 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. CONCLUSION:PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes. Copyright Â
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