The following is a summary of “A germline STAT6 gain-of-function variant is associated with early-onset allergies,” published in the FEBRUARY 2023 issue of Allergy & Immunology by Suratannon, et al.
Inflammation brought on by allergies is mostly regulated by the signal transducer and activator of transcription 6 (STAT6) signaling pathway, which is a signal transducer and activator of transcription. However, no descriptions of STAT6 gain-of-function mutations causing allergies in people have been published. Therefore, in a family of three people with early-onset multiorgan allergies, researchers sought to identify a STAT6 gain-of-function mutation.
T-helper cell subsets’ exomes were sequenced, and immunophenotyping was done. By using Western blot, immunofluorescence, electrophoretic mobility shift assays, and luciferase assays, the STAT6 protein’s function was examined. Studying downstream effector cytokines involved using gastric organoids taken from the index patient.
They discovered a heterozygous missense mutation (c.1129G>A;p.Glu377Lys) in the DNA binding domain of STAT6 that occurred de novo in the father of the index case and was inherited by 2 of his 3 children. Key presentations included severe atopic dermatitis and food allergies. Those who were impacted showed clinical heterogeneity. There were found to be more TH2 lymphocytes in the peripheral blood. Increased DNA binding affinity, a high predilection for nucleus localization, and spontaneous transcriptional activity were all characteristics of the mutant STAT6. Moreover, stomach organoids demonstrated constitutive activation of downstream signaling pathways for STAT6.
An early-onset and severe allergy phenotype in humans was linked to a germline STAT6 gain-of-function mutation that causes spontaneous activation of the STAT6 signaling system. The molecular mechanisms behind allergic illnesses were better understood due to these discoveries, which may also lead to new therapeutic approaches.
Reference: jacionline.org/article/S0091-6749(22)01334-3/fulltext