Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome

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Presentation transcript:

Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome Cristina Woellner, MSc, E. Michael Gertz, PhD, Alejandro A. Schäffer, PhD, Macarena Lagos, MD, Mario Perro, MSc, Erik-Oliver Glocker, MD, Maria C. Pietrogrande, MD, Fausto Cossu, MD, José L. Franco, MD, PhD, Nuria Matamoros, MD, Barbara Pietrucha, MD, PhD, Edyta Heropolitańska-Pliszka, MD, Mehdi Yeganeh, MD, Mostafa Moin, MD, Teresa Español, MD, PhD, Stephan Ehl, MD, Andrew R. Gennery, MD, Mario Abinun, MD, PhD, Anna Bręborowicz, MD, Tim Niehues, MD, Sara Sebnem Kilic, MD, Anne Junker, MD, Stuart E. Turvey, MD, PhD, Alessandro Plebani, MD, Berta Sánchez, PhD, Ben-Zion Garty, MD, Claudio Pignata, MD, Caterina Cancrini, MD, Jiri Litzman, MD, Özden Sanal, MD, Ulrich Baumann, MD, Rosa Bacchetta, MD, Amy P. Hsu, BA, Joie N. Davis, CRNP, Lennart Hammarström, MD, E. Graham Davies, MD, Efrem Eren, MD, Peter D. Arkwright, MD, PhD, Jukka S. Moilanen, MD, PhD, Dorothee Viemann, MD, Sujoy Khan, MRCP, László Maródi, MD, Andrew J. Cant, MD, Alexandra F. Freeman, MD, Jennifer M. Puck, MD, Steven M. Holland, MD, Bodo Grimbacher, MD Journal of Allergy and Clinical Immunology Volume 125, Issue 2, Pages 424-432.e8 (February 2010) DOI: 10.1016/j.jaci.2009.10.059 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Inhibition of TNF-α release in LPS-activated macrophages by IL-10. Macrophages of nine STAT3-mutated patients, 8 of whom had novel mutations, one STAT3 wild-type (wt) patient, and 11 healthy controls were pretreated with IL-10 and then stimulated with LPS. Supernatants were examined for the presence of TNF-α. To ensure better comparability of data from different healthy donors, the impact of IL-10 on TNF-α release is shown as percentage of maximum TNF-α release on LPS stimulation. Journal of Allergy and Clinical Immunology 2010 125, 424-432.e8DOI: (10.1016/j.jaci.2009.10.059) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Percentage of IL-17 (A) and IFN-γ (B) expressing CD4+ memory T cells, determined by intracellular cytokine expression after overnight stimulation with SEB. Each symbol represents the value from an individual donor or patient. Statistical significance was determined with a Wilcoxon rank-sum test. P values are 2-sided. Median values are shown as horizontal bars. wt, Wild-type. Journal of Allergy and Clinical Immunology 2010 125, 424-432.e8DOI: (10.1016/j.jaci.2009.10.059) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Schematic structure of STAT3. Every black dot represents 1 patient carrying the mutation. Patients who carry STAT3 mutations and who were described in previous publications are shown in the upper part of the figure.5,6,13-17 The 64 patients identified in this study who had STAT3 mutations are shown in the lower part. The patient carrying a splice site mutation after exon 22 is shown as having DNA sequence change because the effect on the protein is not known. p.?, Unknown effect on protein level. Journal of Allergy and Clinical Immunology 2010 125, 424-432.e8DOI: (10.1016/j.jaci.2009.10.059) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Two alternative splicing sites, 1 between exons 21 and 22 and 1 between exons 22 and 23, result in 3 alternative wild-type transcripts: 2 STAT3α transcripts (NM_139276, NM_003150) and 1 STAT3β (NM_213662) transcript. The splice site introduced by the mutation 1 nucleotide after exon 22 causes the 43-bp exon 22 to be skipped. In mutant variants of NM_139276 and NM_003150, this deletion would result in a frame shift and a premature stop-codon. In conjunction with the 50-bp shorter exon 23 of STAT3β, the deletion of exon 22 is predicted to produce a transcript that codes for a variant of STAT3α with an in-frame deletion of 31 amino acids. The amino acid sequences of the STAT3α transcripts shared with the mutated STAT3β transcript are highlighted in pink. Journal of Allergy and Clinical Immunology 2010 125, 424-432.e8DOI: (10.1016/j.jaci.2009.10.059) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2010 125, 424-432 Journal of Allergy and Clinical Immunology 2010 125, 424-432.e8DOI: (10.1016/j.jaci.2009.10.059) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2010 125, 424-432 Journal of Allergy and Clinical Immunology 2010 125, 424-432.e8DOI: (10.1016/j.jaci.2009.10.059) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2010 125, 424-432 Journal of Allergy and Clinical Immunology 2010 125, 424-432.e8DOI: (10.1016/j.jaci.2009.10.059) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions