Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase ? syndrome–like immunodeficiency - 18/04/17
, 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, MD i, Yoshihiro Maruo, MD, PhD i, 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, PhD n, Satoshi Okada, MD, PhD d, Masao Kobayashi, MD, PhD d, Tomohiro Morio, MD, PhD c, Shigeaki Nonoyama, MD, PhD aAbstract |
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.
El texto completo de este artículo está disponible en PDF.Graphical abstract |
Key words : Activated phosphatidylinositol 3-kinase δ syndrome, catalytic subunit p110δ of phosphatidylinositol 3-kinase, phosphatase and tensin homolog, primary immunodeficiency disease
Abbreviations used : APDS, BRRS, CS, CVID, FITC, GAPDH, GOF, IVIG, KREC, LOF, mTOR, NK, pAKT, PCP, PET, PID, PI3K, PIP2, PIP3, pmTOR, pS6, PTEN, qPCR, ST, TFH, TrB, TREC
Esquema
| Supported in part by the Ministry of Defense, Japan; the Research on Measures for Intractable Diseases Project (H26-037, H23-012): matching fund subsidy from the Ministry of Health, Labour and Welfare, Japan; the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (26293250, 15K09640); the Practical Research for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, AMED; the Japan Foundation for Pediatric Research; the Jeffrey Modell Foundation; the Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics; and Drs M. and W. Hirose, H. Matsuda, and H. Seto. |
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| Disclosure of potential conflict of interest: K. Imai has received research support from the Japan Foundation for Pediatric Research and CSL Behring KK and has received consultancy and lecture fees from CSL Behring. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 138 - N° 6
P. 1672 - décembre 2016 Regresar al número
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