Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): Chronic mucocutaneous candidiasis accompanied by enamel defects.

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Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): Chronic mucocutaneous candidiasis accompanied by enamel defects and delayed dental shedding Glynis Frans, MPharm, Leen Moens, PhD, Heidi Schaballie, MD, Lien Van Eyck, MD, MSc, Heleen Borgers, PhD, Margareta Wuyts, BSc, Doreen Dillaerts, MSc, Edith Vermeulen, MPharm, James Dooley, PhD, Bodo Grimbacher, MD, PhD, Andrew Cant, MD, PhD, Dominique Declerck, PhD, Marleen Peumans, PhD, Marleen Renard, MD, Kris De Boeck, MD, PhD, Ilse Hoffman, MD, PhD, Inge François, MD, PhD, Adrian Liston, PhD, Frank Claessens, MD, PhD, Xavier Bossuyt, MD, PhD, Isabelle Meyts, MD, PhD Journal of Allergy and Clinical Immunology Volume 134, Issue 5, Pages 1209-1213.e6 (November 2014) DOI: 10.1016/j.jaci.2014.05.044 Copyright © 2014 The Authors Terms and Conditions

Fig 1 Clinical characteristics. A, Growth charts showing severe growth retardation that only picks up after growth hormone therapy and puberty induction with tube feeding overnight. Arrows indicate onset of tube feeding and growth hormone therapy, respectively. B, Computed tomography showing an atonic esophagus (arrow) with air containing paraesophageal diverticula. C, Computed tomography of the chest showing multiple saccular bronchiectases and bronchial wall thickening. D, Atrophy in the duodenum, as seen on endoscopy. E and F, Severe erosive tooth wear, caries, and retained primary teeth. Journal of Allergy and Clinical Immunology 2014 134, 1209-1213.e6DOI: (10.1016/j.jaci.2014.05.044) Copyright © 2014 The Authors Terms and Conditions

Fig 2 The mutant T385M STAT1 allele is a gain-of-phosphorylation and gain-of-function mutation. A, Direct sequence analysis of exon 14 of STAT1 (forward sequence) in a control subject and the patient with a c.1153C>T resulting in p.T385M. B, Intracellular staining of phosphorylated tyrosine 701 STAT1 (STAT1p) in lymphocytes after stimulation with IFN-γ (2000 IU/mL, left panel) or IFN-α (105 IU/mL, right panel) for 15 minutes. STAT1 and STATp are shown in a control subject (red) and in the T385M patient (blue). Unstimulated conditions are represented as dashed lines. Results shown are representative of 2 independent experiments. MFI, Mean fluorescence intensity. C, Evaluation of STAT1, STAT1 phosphorylation, and STAT1p GAS DNA-binding capacity. Fibroblasts derived from wild-type (WT)/WT control subjects (C1 and C2), p.T385M/WT (patient P1), and p.K388E/WT (patient P2) were stimulated with 100 U/mL IFN-α (α) or 100 U/mL IFN-γ (Υ) or left unstimulated (−) for 60 minutes. a, Western blotting was carried out for detection of STAT1 and STAT1p levels in nuclear extracts (5 μg per sample). Heterogeneous nuclear ribonucleoprotein I (hnRNP I) was used as a loading control reference. b, STAT1 GAS DNA-binding capacity was evaluated by using EMSA. One microgram of nuclear extract was preincubated with 20,000 cpm of GAS probe at room temperature before nondenaturing PAGE separating free from STAT-bound probe. Journal of Allergy and Clinical Immunology 2014 134, 1209-1213.e6DOI: (10.1016/j.jaci.2014.05.044) Copyright © 2014 The Authors Terms and Conditions

Fig E1 A, IL-17 production in PBMCs of the T385M patient and a healthy control subject after stimulation with PHA, heat-inactivated C albicans, or heat-inactivated S aureus. Results shown are derived from one representative experiment of 4 independent experiments. B, IFN-γ production in PBMCs of the T385M patient and a healthy control subject after stimulation with PHA, heat-inactivated C albicans, or heat-inactivated S aureus. Results shown are derived from one representative experiment of 4 independent experiments. HKCA, Heat-killed C albicans; HKSA, heat-killed S aureus. Journal of Allergy and Clinical Immunology 2014 134, 1209-1213.e6DOI: (10.1016/j.jaci.2014.05.044) Copyright © 2014 The Authors Terms and Conditions