A germline STAT6 gain-of-function variant is associated with early-onset allergies - 03/02/23
, Pantipa Chatchatee, MD a, j, ⁎ , P. Martin van Hagen, MD, PhD a, j, n, o, q, ⁎ , Vorasuk Shotelersuk, MD b, lAbstract |
Background |
The signal transducer and activator of transcription 6 (STAT6) signaling pathway plays a central role in allergic inflammation. To date, however, there have been no descriptions of STAT6 gain-of-function variants leading to allergies in humans.
Objective |
We report a STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with 3 affected members.
Methods |
Exome sequencing and immunophenotyping of T-helper cell subsets were conducted. The function of the STAT6 protein was analyzed by Western blot, immunofluorescence, electrophoretic mobility shift assays, and luciferase assays. Gastric organoids obtained from the index patient were used to study downstream effector cytokines.
Results |
We identified a heterozygous missense variant (c.1129G>A;p.Glu377Lys) in the DNA binding domain of STAT6 that was de novo in the index patient’s father and was inherited by 2 of his 3 children. Severe atopic dermatitis and food allergy were key presentations. Clinical heterogeneity was observed among the affected individuals. Higher levels of peripheral blood TH2 lymphocytes were detected. The mutant STAT6 displayed a strong preference for nuclear localization, increased DNA binding affinity, and spontaneous transcriptional activity. Moreover, gastric organoids showed constitutive activation of STAT6 downstream signaling molecules.
Conclusions |
A germline STAT6 gain-of-function variant results in spontaneous activation of the STAT6 signaling pathway and is associated with an early-onset and severe allergic phenotype in humans. These observations enhance our knowledge of the molecular mechanisms underlying allergic diseases and will potentially contribute to novel therapeutic interventions.
Le texte complet de cet article est disponible en PDF.Key words : STAT6, gain of function, primary atopic disorders, food allergy, anaphylaxis, atopic dermatitis
Abbreviations used : AD, AEG, CCL, GOF, Mt, STAT, Wt
Plan
| Supported by the Thailand Science Research and Innovation Fund Chulalongkorn University, Thailand (CU_FRB65_hea (35)_042_30_23, HEA663200060), Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University, Thailand (RA56/009), Health Systems Research Institute, Thailand (65-039, 65-040), National Research Council of Thailand, Thailand (NRCT) (N42A650229), internal grant from Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Netherlands. P. J. van der Spek and S.M.A. Swagemakers received funding from the Horizon 2020 program ImmunAID, EU, for bioinformatics services (779295). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 151 - N° 2
P. 565 - février 2023 Retour au numéro
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