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

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Presentation on theme: "Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder  Michael D. Keller, MD, Rahul Pandey, PhD, Dong Li,"— Presentation transcript:

1 Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder 
Michael D. Keller, MD, Rahul Pandey, PhD, Dong Li, PhD, Joseph Glessner, PhD, Lifeng Tian, PhD, Sarah E. Henrickson, MD, PhD, Ivan K. Chinn, MD, Linda Monaco-Shawver, BSc, Jennifer Heimall, MD, Cuiping Hou, BSc, Frederick G. Otieno, MS, Soma Jyonouchi, MD, Leonard Calabrese, DO, Joris van Montfrans, MD, Jordan S. Orange, MD, PhD, Hakon Hakonarson, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 138, Issue 2, Pages e4 (August 2016) DOI: /j.jaci Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 A, IRF2BP2 c. 1652G>A segregated only in family members with a diagnosis of CVID. B, The resulting p.S551N mutation occurs in the RING domain of IRF2BP2 (denoted by the arrow). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 A, Development of B-cell plasmablasts was decreased in the proband versus healthy control subjects 7 days after stimulation with IL-21, CD40 ligand (CD40L), or CpG. B, Plasmablast counts (CD19+CD27+CD38++) at day 7 were decreased in the proband at day 7 versus a healthy control subject. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 A, RT-PCR of IRF2BP2 showed increased transcripts in the proband versus healthy control subjects (vs actin) with agreement between primers specific for exon 1 (present in isoform 1 of IRF2BP2) and exon 2 (present in both isoforms 1 and 2). B, Western blotting showed increased protein expression of IRF2BP2 in lysates of EBV-LCLs from the proband versus control subjects. TATA-binding protein is shown as the loading control. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 A, Nucleofection of human B cells with mutant IRF2BP2 construct (p.S551N) leads to reduced plasmablast formation 7 days after CpG stimulation versus wild-type IRF2BP2 nucleofection, which reached statistical significance (*P < .02). Data shown reflect the mean percentage of plasmablast formation after 7 days of culture and represent 5 duplicate runs. B, On the SVM hyperplane, the proband was predicted to fall in the nonpolygenic region. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig E1 Primer sets for IRF2BP2 were designed for exon 1 (contained in isoforms 1 and 2) and exon 2 (only contained in isoform 2). APC, Allophycocyanin; FITC, fluorescein isothiocyanate; PE, phycoerythrin. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E2 Gating strategy for B-cell plasmablasts. B-cell plasmablasts were identified based on a CD19 gate, followed by gating on the CD27+CD38+ population. Gating was established by using isotype control antibodies. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E3 Damaging variants in the proband with autosomal dominant pattern. After filtering nonsynonymous variants, potentially damaging changes in 12 genes were identified by using whole-exome sequencing in the proband. Three of these (IRF2BP2, PIK3C2G, and PARP1, shown in red) were tied to immunologic pathways. Of these variants, only IRF2BP2 was not identified in the ExAC public database or the Baylor Center for Mendelian Genomics Database. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E4 Phylogenetic conservation of IRF2BP2. Serine-551 of IRF2BP2 is highly conserved across species (from UCSC Genome Browser, Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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