Presentation is loading. Please wait.

Presentation is loading. Please wait.

Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome–like immunodeficiency  Yuki Tsujita, MD, Kanako.

Published byΝικολίτα Παπάγος Modified over 6 years ago

Similar presentations

Presentation on theme: "Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome–like immunodeficiency  Yuki Tsujita, MD, Kanako."— Presentation transcript:

1 Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome–like immunodeficiency  Yuki Tsujita, MD, Kanako Mitsui-Sekinaka, MD, Kohsuke Imai, MD, PhD, Tzu-Wen Yeh, MSc, Noriko Mitsuiki, MD, PhD, Takaki Asano, MD, Hidenori Ohnishi, MD, PhD, Zenichiro Kato, MD, PhD, Yujin Sekinaka, MD, Kiyotaka Zaha, MD, Tamaki Kato, MD, PhD, Tsubasa Okano, MD, Takehiro Takashima, MD, Kaoru Kobayashi, MD, PhD, Mitsuaki Kimura, MD, PhD, Tomoaki Kunitsu, MD, Yoshihiro Maruo, MD, PhD, Hirokazu Kanegane, MD, PhD, Masatoshi Takagi, MD, PhD, Kenichi Yoshida, MD, PhD, Yusuke Okuno, MD, PhD, Hideki Muramatsu, MD, PhD, Yuichi Shiraishi, PhD, Kenichi Chiba, BA, Hiroko Tanaka, BSc, Satoru Miyano, PhD, Seiji Kojima, MD, PhD, Seishi Ogawa, MD, PhD, Osamu Ohara, PhD, Satoshi Okada, MD, PhD, Masao Kobayashi, MD, PhD, Tomohiro Morio, MD, PhD, Shigeaki Nonoyama, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 138, Issue 6, Pages e10 (December 2016) DOI: /j.jaci Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Journal of Allergy and Clinical Immunology 2016 138, 1672-1680
Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 1 Family tree of patients given a diagnosis of PID. Black boxes and circles represent patients with identified or suspected disease-causing mutations. An identification number has been assigned to each patient (P1-P9). Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 2 PET scanning of P1 and P6 after administration of the glucose analog 18F-fludeoxyglucose. A, Increased glucose uptake was observed in cervical and abdominal lymph nodes and in spleen tissue from P1. B, Increased glucose uptake was observed in cervical, abdominal, and axillary lymph nodes from P6. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 3 DNA electropherogram of the PTEN gene, PTEN gene expression, and abundance of PTEN protein. A, DNA electropherogram shows the position of the mutation in PTEN (arrow). B, PTEN gene expression in P1 versus a healthy control subject (n = 1; error bars indicate SD of triplicate qPCR data), as normalized to ACTB gene expression levels. C, PTEN and GAPDH expression was measured by using immunoblotting in activated T-cell lysates from patients P1 to P4 and healthy control subjects. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 4 Hyperphosphorylation of AKT, mTOR, and S6 ribosomal protein in patients and healthy control subjects. A, Immunoblot analysis of AKT phosphorylation at Ser473 (pAKT[S473]), total AKT, S6 ribosomal protein phosphorylated at Ser235 and Ser236 (pS6[S235,236]), and GAPDH (loading control) in activated T cells. B, Multiplex assays of phosphorylation levels of pAKT(S473)/GADPH, pmTOR (S2448)/GADPH, and pS6(S235, S236)/GADPH in activated T cells. Fig 4, A, shows representative data of P1 (PTEN), P5 (PIK3CD E1021K), and P9 (PIK3CD E525A) and their controls (n = 1). In Fig 4, B, Data from patients with PTEN, PIK3CD E1021K, and PIK3CD E525A mutations are shown relative to those from healthy control subjects (n = 3, 2, and 1, respectively). C, Hyperphosphorylation of AKT in patients and healthy control subjects. Phosphorylation of pAKT in B cells in the resting state shown by using Phosflow analysis (red solid lines) and phosphorylation of pAKT in B cells from patients and healthy control subjects treated with p110δ inhibitor (black dotted lines). Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 5 Schematic representation. GOF mutations in PIK3CD favor the conversion of PIP2 to PIP3 and enhance phosphorylation of AKT, mTOR, and S6 proteins. Similarly, loss of PTEN function suppresses the inhibitory function of PI3K, which enhances protein phosphorylation in the AKT/mTOR/S6 pathway. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E1 Analysis algorithm for whole-exome sequencing data and location of the pathogenic PTEN mutation in P1. A data analysis algorithm was used to filter all single nucleotide variants and insertion-deletion variants. Numbers of variants identified by using exome-wide sequencing are shown for each filtering step. Although variations in 2 other genes (B3GALT2 and PIEZO2) were also annotated by using whole-exome sequencing, they were not considered to be involved in the disease because both were missense variations and the mutated genes were not related to the immune system. SNP, Single nucleotide polymorphism. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E2 DNA electropherograms of PIK3CD and a structural model of human PI3K. A, Novel mutations in the PIK3CD gene were identified in 3 related patients (P7-P9). DNA electropherograms show the position of the mutation (arrow). B and C, Normal structure (E525) showing interactions between p110δ (blue) and the inter-SH2 (iSH2) and C-terminal SH2 (cSH2) domains of p85α (orange). D, Reported mutation (E525K). E, Novel mutation (E525A). Positive and negative charges are shown with red and blue sticks, respectively. Functional prediction algorithms (SIFT and MutationTaster) indicated that the novel E525A mutation might be deleterious. Moreover, in agreement with a previous report of the E525K mutation,E2 the new PIK3CD (E525A) mutation was associated with a loss of hydrogen bonds between the p85α and p110δ subunits, resulting in decreased binding affinity. In addition, hydrogen bonds in the p110δ molecule were lost, resulting in decreased stability of the peripheral p110δ subunit, as indicated by using protein structure analysis. Mutations of A525 are less likely to affect steric hindrance because of the small size of the p110δ subunit. However, binding affinity is decreased because of the loss of negatively charged residues (Fig E2, E). In contrast, mutations of K525 introduce positive charges that cause repulsive intermolecular forces (Fig E2, D). Thus both p110δ mutations are expected to weaken binding to p85α and contribute to pathogenesis. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E3 Relative units of phosphorylation for AKT (Ser473), mTOR (Ser2448), and S6 (Ser235 and Ser236) by using multiplex assays of P2-P4 and P6-P8. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E4 Hyperphosphorylation of AKT in P2-P4, P6-P8 and healthy control subjects. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Fig E5 Representative flow cytometric analysis of TFH and TrB cells in patients with PIDs. A, Fluorescence-activated cell sorting analysis of CD4+CD3+CD45+CACR5+ TFH cells of patients with PIDs with PIK3CD and PTEN mutations and patients with CVID. B, Representative flow cytometric data of TFH cells in 3 patients of each group. C, Fluorescence-activated cell sorting analysis of CD19+CD24++CD38++ TrB cells of patients with PIDs with PIK3CD and PTEN mutations and control subjects with CVID. D, Representative flow cytometric data of TrB cells in 3 patients of each group. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 Fig E6 Classification of patients given a diagnosis of PID according to TREC/KREC levels. A, Patients were classified as follows: TREC+/KREC+: P1-P4, P7, and P9 and TREC−/KREC+: P5, P6, and P8. B, P7 and P9 were classified as TREC+/KREC+, and P8 was classified as TREC−/KREC+. C, P5 was classified as TREC+/KREC+ as a 5-year-old and as TREC−/KREC+ as an 8-year-old. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Download ppt "Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome–like immunodeficiency  Yuki Tsujita, MD, Kanako."

Similar presentations

LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency  Abdullah Alangari, MD,

LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency  Abdullah Alangari, MD,
Janet Chou, MD, Yousef R. Badran, MD, Christina S. K

Janet Chou, MD, Yousef R. Badran, MD, Christina S. K
Upregulation of miR-18a-5p contributes to epidermal necrolysis in severe drug eruptions  Asako Ichihara, MD, PhD, Zhongzhi Wang, PhD, Masatoshi Jinnin,

Upregulation of miR-18a-5p contributes to epidermal necrolysis in severe drug eruptions  Asako Ichihara, MD, PhD, Zhongzhi Wang, PhD, Masatoshi Jinnin,
Critical link between glycogen synthase kinase 3β and forkhead box P3 in patients with chronic rhinosinusitis with nasal polyps  Xingmei Wu, MD, Sihua.

Critical link between glycogen synthase kinase 3β and forkhead box P3 in patients with chronic rhinosinusitis with nasal polyps  Xingmei Wu, MD, Sihua.
Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants  Reiko Kagawa,

Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants  Reiko Kagawa,
Diffuse large B-cell lymphoma as presenting feature of Zap-70 deficiency  Andrea Newell, BSc, Harjit Dadi, PhD, Rachel Goldberg, BSc, Bo-Yee Ngan, MD,

Diffuse large B-cell lymphoma as presenting feature of Zap-70 deficiency  Andrea Newell, BSc, Harjit Dadi, PhD, Rachel Goldberg, BSc, Bo-Yee Ngan, MD,
Defects of class-switch recombination

Defects of class-switch recombination
A novel splice variant of FcγRIIa: A risk factor for anaphylaxis in patients with hypogammaglobulinemia  Joris van der Heijden, MSc, Judy Geissler, Edwin.

A novel splice variant of FcγRIIa: A risk factor for anaphylaxis in patients with hypogammaglobulinemia  Joris van der Heijden, MSc, Judy Geissler, Edwin.
Identification and gene cloning of a new major allergen Cha o 3 from Chamaecyparis obtusa (Japanese cypress) pollen  Toshihiro Osada, MSc, Takafumi Harada,

Identification and gene cloning of a new major allergen Cha o 3 from Chamaecyparis obtusa (Japanese cypress) pollen  Toshihiro Osada, MSc, Takafumi Harada,
Proviral integration site for Moloney murine leukemia virus 1, but not phosphatidylinositol-3 kinase, is essential in the antiapoptotic signaling cascade.

Proviral integration site for Moloney murine leukemia virus 1, but not phosphatidylinositol-3 kinase, is essential in the antiapoptotic signaling cascade.
Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders  Tomonori Kadowaki, MD, Hidenori Ohnishi, MD, PhD, Norio Kawamoto, MD, PhD,

Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders  Tomonori Kadowaki, MD, Hidenori Ohnishi, MD, PhD, Norio Kawamoto, MD, PhD,
The C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B-cell homeostasis in heterozygous.

The C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B-cell homeostasis in heterozygous.
Combined DOCK8 and CLEC7A mutations causing immunodeficiency in 3 brothers with diarrhea, eczema, and infections  Darrell L. Dinwiddie, PhD, Stephen F.

Combined DOCK8 and CLEC7A mutations causing immunodeficiency in 3 brothers with diarrhea, eczema, and infections  Darrell L. Dinwiddie, PhD, Stephen F.
Analysis of somatic hypermutations in the IgM switch region in human B cells  Katsuyuki Horiuchi, MD, PhD, Kohsuke Imai, MD, PhD, Kanako Mitsui-Sekinaka,

Analysis of somatic hypermutations in the IgM switch region in human B cells  Katsuyuki Horiuchi, MD, PhD, Kohsuke Imai, MD, PhD, Kanako Mitsui-Sekinaka,
Lucia Elena Alvarado Arnez, BS, Evaristo N

Lucia Elena Alvarado Arnez, BS, Evaristo N
Chronic mucocutaneous candidiasis associated with an SH2 domain gain-of-function mutation that enhances STAT1 phosphorylation  Ali Sobh, MD, Janet Chou,

Chronic mucocutaneous candidiasis associated with an SH2 domain gain-of-function mutation that enhances STAT1 phosphorylation  Ali Sobh, MD, Janet Chou,
Persistence of the IgE repertoire in birch pollen allergy

Persistence of the IgE repertoire in birch pollen allergy
Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia  Geraldine Aubert, PhD,

Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia  Geraldine Aubert, PhD,
Dorothy M. Ryan, MD, Stephen J. Fowler, MD, Robert M. Niven, MD 

Dorothy M. Ryan, MD, Stephen J. Fowler, MD, Robert M. Niven, MD 
Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association  Christina S. Yee,

Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association  Christina S. Yee,

Similar presentations

Ads by Google