Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.

TitleIndividuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.
Publication TypeJournal Article
Year of Publication2024
AuthorsHoresh, ME, Martin-Fernandez, M, Gruber, C, Buta, S, Le Voyer, T, Puzenat, E, Lesmana, H, Wu, Y, Richardson, A, Stein, D, Hodeib, S, Youssef, M, Kurowski, JA, Feuille, E, Pedroza, LA, Fuleihan, RL, Haseley, A, Hovnanian, A, Quartier, P, Rosain, J, Davis, G, Mullan, D, Stewart, O'J, Patel, R, Lee, AE, Rubinstein, R, Ewald, L, Maheshwari, N, Rahming, V, Chinn, IK, Lupski, JR, Orange, JS, Sancho-Shimizu, V, Casanova, J-L, Abul-Husn, NS, Itan, Y, Milner, JD, Bustamante, J, Bogunovic, D
JournalJ Exp Med
Date Published2024 Jun 03
KeywordsAutoimmunity, Colitis, Dermatitis, Humans, Hypersensitivity, Inflammation, Janus Kinase 1

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.

Alternate JournalJ Exp Med
PubMed ID38563820
PubMed Central IDPMC10986756
Grant ListR01 AI148963 / AI / NIAID NIH HHS / United States
T32 AI078892 / AI / NIAID NIH HHS / United States
T32 GM007280 / GM / NIGMS NIH HHS / United States
5T32GM007280 / GM / NIGMS NIH HHS / United States

Similar Publications