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Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation  Despina Moshous,

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Presentation on theme: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation  Despina Moshous,"— Presentation transcript:

1 Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation  Despina Moshous, MD, PhD, Emmanuel Martin, PhD, Wassila Carpentier, PhD, Annick Lim, PhD, Isabelle Callebaut, PhD, Danielle Canioni, MD, PhD, Fabian Hauck, MD, Jacek Majewski, PhD, Jeremy Schwartzentruber, MSc, Patrick Nitschke, PhD, Nicolas Sirvent, MD, PhD, Pierre Frange, MD, Capucine Picard, MD, PhD, Stéphane Blanche, MD, Patrick Revy, PhD, Alain Fischer, MD, PhD, Sylvain Latour, PhD, Nada Jabado, MD, PhD, Jean-Pierre de Villartay, PhD  Journal of Allergy and Clinical Immunology  Volume 131, Issue 6, Pages e9 (June 2013) DOI: /j.jaci Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Genetic analysis of coronin-1A deficiency in a consanguineous family. A, Pedigree of the 3 patients and genetic approach used to identify the disease-causing mutation. B, Homozygous 717 G > A change in the CORO1A gene in the 3 patients found to be heterozygous in both parents. C, Schematic representation of CORO1A, including noncoding (light red) and coding (dark red) exons on the top, the major structural protein domains in the middle, and the position of the V134M localized at the edge of blade 3 at the bottom. CC, Coiled-coil domain; CE, C-terminal extension; NE, N-terminal extension; U, unique region. D, Multiple sequence alignment of coronin-1A from different species. E, Ribbon representation of the 3-dimensional structure of mouse Coronin-1 (Protein Data bank [pdb] 2b4e)9 showing a top (left) and a side (right) view of the β-propeller. Ribbons are rainbow colored from the N- to the C-termini. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Histologic analysis of EBV-associated B-cell lymphoproliferation. Histologic features of a biopsy specimen from patient P1's orbital mass. Patient P2's and P3's cervical lymph node biopsy specimens show B-cell lymphoproliferation. Staining with hematoxylin and eosin (HE) and immunostaining with CD20 demonstrates the CD20+ lymphocyte infiltration. Numerous nuclei are stained on in situ hybridization with an EBER probe. The right panels show patient P3's biopsy specimen stained with CD3, CD30, and the proliferative marker Ki67, as indicated. Original magnification ×400. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Loss of naive iNKT and MAIT cells in patients with coronin-1A deficiency. A, iNKT cells were virtually absent in patient P1 compared with numbers seen in a healthy control subject. Patient P1 has been tested for NKT cells several times over a period of 3 years (between ages 8 and 11 years). Results were superimposable. B, MAIT cell numbers from patient P1 compared with those from a healthy control subject were also significantly decreased. C, Patients' iNKT and MAIT cell numbers compared with the results of a group of healthy control subjects. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Immunoscopic analysis of the TCR repertoire: profiles of TCR Vβ (A), Vγ (B), and Vδ (C). Bias in the use of TCRβV4, as well as numerous cell expansions, in patient P1 analyzed at the age of 8 years (6 years after lymphoproliferation). Reduced diversity of the TCRγ/δ repertoire, with an increase in the Vδ3, Vδ8, and Vγ5 populations and numerous cell expansions. Patient P3 was analyzed once at the onset of lymphoproliferation at the age of 16 months. The TCR-Vβ repertoire did not show any evident bias, but the diversity was decreased and numerous cell expansions were present, whereas several Vβ families could not be detected (BV5, BV6, and BV7a). Although the TCR γ/δ repertoire was more diverse in patient P3 than in patient P1, it showed significant alterations in patient P3, with an increase in the Vδ6 and Vγ8 populations and numerous cell expansions. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Functional effect of the V134M mutation. A, Expression of CORO1A mRNA assessed by using quantitative real-time PCR. B, Immunoblot of total cell lysates of PBLs (left) and T-cell blasts (right) from patient P1, his mother, and a healthy control subject stained with coronin-1A–specific polyclonal antibodies. GAPDH expression, as shown in the lower part of the membrane with anti-GAPDH antibody, indicates equal loading. C, Flow cytometric expression of coronin-1A protein in the PBLs from patient P1, his mother, and a healthy control subject. D, Flow cytometric expression of coronin-1A protein in memory versus naive T cells from patient P1 and a healthy control subject. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E1 Chest computed tomographic scans in patient P3 and control subjects. The scan shows the presence of thymic tissue in patient P3 at the age of 15 months compared with computed tomographic scans of patients with SCID at different ages, a healthy child, and a patient with leaky SCID. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E2 Tyrosine phosphorylation on TCR triggering in V134M and control T-cell blasts. Immunoblotting of lysates from control (left) or V134M (right) T-cell blasts stimulated with OKT3 at a concentration of 1 μg/mL for the times indicated. Proteins were separated by means of SDS-PAGE (10%) and immunoblotted with anti-phosphotyrosine (upper panel), anti–phospho-ERK1/2 (middle panel), or anti-actin (lower panel). Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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