Morpholino-based correction of hypomorphic ZAP70 mutation in an adult with combined immunodeficiency Christina Gavino, MSc, Marija Landekic, MSc, Jibin.

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Morpholino-based correction of hypomorphic ZAP70 mutation in an adult with combined immunodeficiency Christina Gavino, MSc, Marija Landekic, MSc, Jibin Zeng, PhD, Ning Wu, PhD, Sungmi Jung, MD, Ming-Chao Zhong, PhD, Alexis Cohen-Blanchet, MSc, Mélanie Langelier, BScN, Odile Neyret, PhD, Duncan Lejtenyi, MSc, Claudia Rochefort, MD, Judith Cotton- Montpetit, BSc, Christine McCusker, MD, Bruce Mazer, MD, André Veillette, MD, Donald C. Vinh, MD Journal of Allergy and Clinical Immunology Volume 139, Issue 5, Pages 1688-1692.e10 (May 2017) DOI: 10.1016/j.jaci.2017.02.002 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, The c.1272C>T ZAP-70–altered splice site. B, Electropherograms from a healthy control (HC), P1, and P1's family. C, RT-PCR products from an HC, P1, and P1's family. D, Summary of densitometry analysis. E, Immunoblot of ZAP-70wt or ZAP-70mut transfected cells. F, The AMO binding site within the ZAP-70 pre-mRNA. An asterisk denotes the c.1272C>T mutation. G, RT-PCR products of AMO-treated P1 PBMCs. Journal of Allergy and Clinical Immunology 2017 139, 1688-1692.e10DOI: (10.1016/j.jaci.2017.02.002) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A, AMO-treated PBMCs from a healthy control (HC) or P1 stimulated with OKT3, with densitometry analysis summarized in B. C, AMO-treated HC or P1 PBMCs stimulated with CD3/CD28 as indicated. D, CFSE profiles of HC or P1 CD3/CD28-stimulated T cells, with percentages summarized in E. One experiment representative of at least 2 independent experiments is shown. CFSE, Carboxyfluorescein succinimidyl ester. *P < .05. Journal of Allergy and Clinical Immunology 2017 139, 1688-1692.e10DOI: (10.1016/j.jaci.2017.02.002) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 A, P1 pedigree. An older brother had a papulo-squamous rash at age 1 month, recurrent otitis media, and died at 15 months following recurrent seizures, suspected to be viral encephalitis by imaging, electroencephalogram, and autopsy. B, During P1's first 2 years of life, summaries of investigations revealed decreased CD8+ T lymphocytes with very low T-cell mitogen (PHA and concanavailin A) proliferative responses. B lymphocytes were quantitatively normal with preserved proliferation in response to pokeweed mitogen. Circulating immunoglobulin concentrations (IgG, IgA, IgM) were normal, with IgE occasionally being slightly elevated. Subsequent investigations found no evidence of adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) deficiency with normal expression of HLA on B cells. C, T-cell lysates from P1 and a healthy control (HC) were analyzed by immunoblot with indicated antibodies. Journal of Allergy and Clinical Immunology 2017 139, 1688-1692.e10DOI: (10.1016/j.jaci.2017.02.002) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 A, Well-circumscribed pink macules on the trunk torso. B, Hematoxylin and eosin stain demonstrating enlarged superficial keratinocytes with distinctive blue-gray cytoplasm in association with prominent keratohyaline granules, consistent with HPV infection. C, Immunohistochemical pan-HPV stain. Journal of Allergy and Clinical Immunology 2017 139, 1688-1692.e10DOI: (10.1016/j.jaci.2017.02.002) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 A, A schematic representation of the ZAP-70 protein, with the asterisk denoting the location of the c.1272C>T mutation. B, Jurkat P116 cells were stimulated with OKT3 antibody and cell lysates were analyzed by immunoblot using antibodies specific for LAT and phospho-LAT. LAT, Linker for activation of T cells. Journal of Allergy and Clinical Immunology 2017 139, 1688-1692.e10DOI: (10.1016/j.jaci.2017.02.002) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Gating strategy for assessment of T-cell proliferation of CFSE-labeled, CD3/CD28-stimulated cells. APC, Allophycocyanin; CFSE, carboxyfluorescein succinimidyl ester; FITC, fluorescein isothiocyanate; PE, phycoerythrin. Journal of Allergy and Clinical Immunology 2017 139, 1688-1692.e10DOI: (10.1016/j.jaci.2017.02.002) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions