title: Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency.
abstract: 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.
  
  
  
  This study aimed to identify novel genes responsible for APDS.
  
  
  
  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.
  
  
  
  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.
  
  
  
  PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tsujita
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Mitsui-Sekinaka
authors.affiliation: 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.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Tzu-Wen
authors.initials: TW
authors.lastname: Yeh
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Mitsuiki
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Takaki
authors.initials: T
authors.lastname: Asano
authors.affiliation: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ohnishi
authors.affiliation: 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.
authors.forename: Zenichiro
authors.initials: Z
authors.lastname: Kato
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Sekinaka
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Zaha
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Okano
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takashima
authors.affiliation: Department of Surgery, Kuma Hospital, Kobe, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Allergy and Clinical Immunology, Shizuoka Children's Hospital, Shizuoka, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kunitsu
authors.affiliation: Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Maruo
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pediatrics, Nagoya University Gradual School of Medicine, Nagoya, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Pediatrics, Nagoya University Gradual School of Medicine, Nagoya, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Muramatsu
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: 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.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Pediatrics, Nagoya University Gradual School of Medicine, Nagoya, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Technology Development, Kazusa DNA Research Institute, Chiba, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation; D000081207:Primary Immunodeficiency Diseases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000070876:Tensins / Q000378:metabolism
chemical_list: D000070876:Tensins; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Activated phosphatidylinositol 3-kinase δ syndrome; catalytic subunit p110δ of phosphatidylinositol 3-kinase; phosphatase and tensin homolog; primary immunodeficiency disease