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

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Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association Christina S. Yee, MD, PhD, Michel J. Massaad, PhD, Wayne Bainter, BA, Toshiro K. Ohsumi, PhD, Niko Föger, PhD, Andrew C. Chan, MD, PhD, Nurten A. Akarsu, MD, Caner Aytekin, MD, Deniz Çagdas Ayvaz, MD, PhD, Ilhan Tezcan, MD, PhD, Özden Sanal, MD, Raif S. Geha, MD, Janet Chou, MD Journal of Allergy and Clinical Immunology Volume 137, Issue 3, Pages 879-888.e2 (March 2016) DOI: 10.1016/j.jaci.2015.08.020 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Cutaneous warts and family pedigree. A, Severe cutaneous warts in patient 1. B, Family pedigree. Solid symbols, Affected and homozygous for the p.S401fs mutant; half-solid symbols, carrier for the p.S401fs mutant. Journal of Allergy and Clinical Immunology 2016 137, 879-888.e2DOI: (10.1016/j.jaci.2015.08.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Sanger sequencing of the CORO1A mutation and analysis of the CORO1Ap.S401fs mutant. A, Sanger sequencing demonstrating the CORO1A mutation (1191_1192insC) in the homozygous state in the patients and in the heterozygous state in their mother. Sequencing of a control subject is included. B, Schematic of WT and mutant (Mut) CORO1A. The CORO1AS401fs has the last C-terminal 61 amino acids replaced by a novel 91-amino-acid sequence. C, Immunoblot analysis of CORO1A in lysates of EBV-transformed B cells from a control subject (NL), patients 1 and 2 (P1 and P2), and the patient's mother (M). The mutant CORO1AS401fs (Mut) migrates at a higher molecular weight. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. D, Quantitative analysis of protein expression. The CORO1A/GAPDH ratio from the patients' cells was normalized to that of a control subject to calculate relative CORO1A expression. Columns and bars represent means and SEs and are representative of 3 experiments. Journal of Allergy and Clinical Immunology 2016 137, 879-888.e2DOI: (10.1016/j.jaci.2015.08.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Oligomerization and cytoskeletal distribution of the CORO1AS401fs mutant. A, Coimmunoprecipitation of WT and mutant (Mut) CORO1A in lysates from HEK293T cells cotransfected with combinations of Myc- and FLAG-tagged WT and Mut-CORO1A and FLAG-tagged PYK2 as a negative control. Myc- and FLAG immunoprecipitates (IP) and total cell lysates were immunoblotted with anti-Myc antibody. B, Immunoblot analysis of CORO1A in cytosolic and cytoskeletal fractions from EBV-B cells of a healthy control subjects (NL) or patient (P1). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and PARP were immunoblotted as markers for cytosolic and cytoskeleton-associated proteins, respectively. C, Quantification of CORO1A distribution in the cytosolic and cytoskeletal fractions. Columns and bars represent means and SEs of 2 independent experiments. *P < .05. D, Assessment of F-actin content in CD4+ and CD8+ T cells of patients (P1 and P2) and control subjects (NL1 and NL2). Left, Representative flow cytometric analysis of phalloidin staining. Right, Quantification of F-actin content. Columns and bars represent means and SEs in 2 patients and 2 control subjects. **P < .01. Journal of Allergy and Clinical Immunology 2016 137, 879-888.e2DOI: (10.1016/j.jaci.2015.08.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 CORO1AS401fs results in decreased thymic output and increased peripheral T-cell apoptosis but does not affect calcium flux or cytotoxicity in vitro. A, Flow cytometric analysis of CD4+CD31+CD45RA+ recent thymic emigrants in the patients and a control subject. Cells were gated on CD4+ T cells. B, Cell-surface Annexin V+ in CD4+ T cells in patients (solid bars) or control subjects (open bars) cultured with medium or PHA for 48 hours, as assessed by using flow cytometry. Results represent means and SEs of the percentage of Annexin V+ cells in 2 patients and 5 healthy control subjects. C, Flow cytometry of Annexin V+ binding to CD4+ WT T cells versus Coro1a−/− T cells transduced with a lentivirus vector encoding for WT CORO1A or CORO1AS401fs and ZsGreen fluorescent protein. Cells are gated on CD4+ZsGreen+ cells. Data are representative of 4 mice for each genotype done in 2 different experiments. D, Calcium flux in CD4+ (top panel) and CD8+ (middle panel) cells stimulated with anti-CD3 from patients. Lower panel, NK cell calcium flux after anti-CD56 stimulation. Patient 1, Blue; patient 2, red; healthy control subject, black. E, Cytotoxic cell killing of K562 target cells by PBMCs in the 51Cr release assay. The means and SEs of 4 replicates are shown. ns, Not significant. F, CD107a expression on CD3−CD56+ NK cells after stimulation with K562 target cells. G, CD107a expression on CD3+CD8+ cells after anti-CD3 stimulation. For Fig 4, E and F, percentages of stimulated CD107ahigh cells are shown. Graphs show means and SEs for 2 independent experiments. Journal of Allergy and Clinical Immunology 2016 137, 879-888.e2DOI: (10.1016/j.jaci.2015.08.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Expression of T-cell activation markers and IL-2 secretion after T-cell stimulation. A, Flow cytometric analysis of CD25 (left) and CD69 (right) on PBMCs after 2 days of stimulation with PHA or anti-CD3 antibody. M, Media. B, IL-2 secretion by PBMCs after 2 days of stimulation with PHA or anti-CD3. Graphs show means and SEs from 2 control subjects and 2 patients. By using the Student t test, there was no significant difference between the patients and control subjects with regard to CD25 expression, CD69 expression, or IL-2 production under any of the culture conditions. Journal of Allergy and Clinical Immunology 2016 137, 879-888.e2DOI: (10.1016/j.jaci.2015.08.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions