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

Slides:

Advertisements

Similar presentations

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

Advertisements

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,

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,

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

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,

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,

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.

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

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

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

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

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

Flow cytometric measurement of STAT1 and STAT3 phosphorylation in CD4+ and CD8+ T cells—clinical applications in primary immunodeficiency diagnostics

Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder Michael D. Keller, MD, Rahul Pandey, PhD, Dong Li,

CD19 controls Toll-like receptor 9 responses in human B cells

Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome Masatoshi Takagi, MD, PhD, Shohei Ogata,

RNA sequencing reveals the consequences of a novel insertion in dedicator of cytokinesis-8 Shaheen Khan, PhD, Merin Kuruvilla, MD, David Hagin, MD, PhD,

Distinct mutations at the same positions of STAT3 cause either loss or gain of function Prabha Chandrasekaran, PhD, Ofer Zimmerman, MD, Michelle Paulson,

Modification of cellular and humoral immunity by somatically reverted T cells in X-linked lymphoproliferative syndrome type 1 Akihiro Hoshino, MD, PhD,

Janet Chou, MD, Yousef R. Badran, MD, Christina S. K

Mechanisms of tissue inhibitor of metalloproteinase 1 augmentation by IL-13 on TGF- β1–stimulated primary human fibroblasts Xiuxia Zhou, PhD, Haizhen.

The Wiskott-Aldrich syndrome

Clinical characteristics and genotype-phenotype correlations in C3 deficiency Yuka Okura, MD, PhD, Ichiro Kobayashi, MD, PhD, Masafumi Yamada, MD, PhD,

The usefulness of measuring tear periostin for the diagnosis and management of ocular allergic diseases Hiroshi Fujishima, MD, Naoko Okada, PhD, Kenji.

Jia Guo, MD, Xin Lin, PhD, Marc A

A network-based analysis of the late-phase reaction of the skin

Interleukin receptor-associated kinase-4 deficiency impairs Toll-like receptor–dependent innate antiviral immune responses Douglas R. McDonald, MD, PhD,

Application of extensively targeted next-generation sequencing for the diagnosis of primary immunodeficiencies Daiei Kojima, MD, Xinan Wang, MD, Hideki.

T-box 21 transcription factor is responsible for distorted TH2 differentiation in human peripheral CD4+ T cells Osamu Kaminuma, DVM, PhD, Fujiko Kitamura,

Profiling of human CD4+ T-cell subsets identifies the TH2-specific noncoding RNA GATA3-AS1 Huan Zhang, MD, PhD, Colm E. Nestor, PhD, Shuli Zhao, PhD,

Fibronectin is a TH1-specific molecule in human subjects

Genetic variation in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway affects contact hypersensitivity responses Julien.

Cigarette smoke combined with Toll-like receptor 3 signaling triggers exaggerated epithelial regulated upon activation, normal T-cell expressed and secreted/CCL5.

Sequencing the IL4 locus in African Americans implicates rare noncoding variants in asthma susceptibility Gabe Haller, BA, Dara G. Torgerson, PhD, Carole.

Donald W. MacGlashan, MD, PhD, Sarbjit S. Saini, MD

Elucidating the effects of disease-causing mutations on STAT3 function in autosomal- dominant hyper-IgE syndrome Simon J. Pelham, MSc, Helen C. Lenthall,

Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations Akihiro Hoshino, MD, PhD, Satoshi Okada, MD, PhD, Kenichi Yoshida,

Emma L. Wise, PhD, Kandace T. Bonner, BSc, Timothy J

Dominant negative CARD11 mutations: Beyond atopy

Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1) Kornvalee Meesilpavikkai,

Antisense molecules: A new class of drugs

Food allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention, and management Scott H. Sicherer, MD, Hugh A. Sampson, MD Journal.

Early and late B-cell developmental impairment in nuclear factor kappa B, subunit 1– mutated common variable immunodeficiency disease Vassilios Lougaris,

Manfred Fliegauf, PhD, Bodo Grimbacher, MD

Weiguo Chen, PhD, Gurjit K. Khurana Hershey, MD, PhD

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

Extrapulmonary tuberculosis mimicking Mendelian susceptibility to mycobacterial disease in a patient with signal transducer and activator of transcription.

Autophagy: Nobel Prize 2016 and allergy and asthma research

Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment

A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome Hidenori Ohnishi, MD, PhD, Rie Miyata, MD,

Quantification of κ-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects Noriko Nakagawa,

Primary immunodeficiency disorder caused by phosphoinositide 3–kinase δ deficiency Georgios Sogkas, MD, PhD, Mykola Fedchenko, MD, Akshay Dhingra, MSc,

Katie Frith, MD, Anne-Laure Joly, PhD, Cindy S. Ma, PhD, Stuart G

TH9 immunodeficiency in patients with hyper-IgE syndrome

Siobhan O. Burns, MD, PhD, Helen L

Genome-wide association study reveals class I MHC–restricted T cell–associated molecule gene (CRTAM) variants interact with vitamin D levels to affect.

Pradeep Reddy Marri, PhD, Debra A. Stern, MS, Anne L

A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency

Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin κ-deleting recombination excision circles Chikako Kamae,

Natural history of cow’s milk allergy

Combined immunodeficiency in a patient with c-Rel deficiency

Presentation transcript:

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 1672-1680.e10 (December 2016) DOI: 10.1016/j.jaci.2016.03.055 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2016 138, 1672-1680 Journal of Allergy and Clinical Immunology 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Hyperphosphorylation of AKT in P2-P4, P6-P8 and healthy control subjects. Journal of Allergy and Clinical Immunology 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2016 138, 1672-1680.e10DOI: (10.1016/j.jaci.2016.03.055) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions