Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.
Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.
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携带 JAK1 变异的个体会受到自身免疫、特应性、结肠炎和皮炎等综合征特征的影响。
DOI：
10.1084/jem.20232387
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发表时间：
2024
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作者：
Horesh,MichaelE;Martin-Fernandez,Marta;Gruber,Conor;Buta,Sofija;LeVoyer,Tom;Puzenat,Eve;Lesmana,Harry;Wu,Yiming;Richardson,Ashley;Stein,David;Hodeib,Stephanie;Youssef,Mariam;Kurowski,JacobA;Feuille,Elizabeth;Pedroza,LuisA;
Inborn errors of immunity (IEI) are a group of heterogeneous disorders that affect the establishment, homeostasis, and/or regulation of the immune system. They are caused by germline mutations in immune or immune-regulatory genes and can result in early-onset severe infections, autoimmunity, autoinflammation, allergy, and/or malignancy (Tangye et al., 2022). The unique causative genetic variants are thought to range from exceedingly rare (private) to ultrarare (minor allele frequency [MAF]< 0.1%); however, current studies estimate the aggregate frequency of these disorders to be between ultrarare and rare (0.1%> MAF< 1%), affecting nearly 1 in 1,000 individuals and accounting for a growing healthcare burden (Picard et al., 2015; Tangye et al., 2020, 2022).The JAK–STAT pathway encompasses an evolutionarily conserved signaling cascade by which cells respond to exogenous ligands and transmit their signals into transcriptional regulation, thereby orchestrating various biological functions including cell growth, differentiation, innate immune sensing, and adaptive immune activation. In brief, the pathway starts with the engagement of a transmembrane receptor by an extracellular ligand, which triggers dimerization or oligomerization of partnering receptors. This induces the preassociated Janus kinases (JAK1-4, TYK2) to cis-and trans-phosphorylate tyrosine residues of their own and the partnering receptor–JAK complexes. This phosphorylation signature induces the recruitment of signal transducer and activator of transcription (STAT1-4, STAT5a–b, STAT6) protein monomers, which are also phosphorylated, enabling the formation of homo-or heterodimers. These active STAT–STAT complexes then translocate to the nucleus where they initiate specific gene expression programs that carry out the desired cellular response. Within the JAK–STAT pathway, JAK1 stands out as a master regulator of the cascade in that it mediates signals for at least 28 different cytokines, accounting for almost half of all ligands that signal through the JAK–STAT pathway (Hammarén et al., 2019). The JAK1 gene (chr1: 64,833,223-65,067,754; GRCh38/hg38) encodes a broadly expressed mRNA transcript that is translated into an evolutionarily conserved tyrosine kinase consisting of four core domains—FERM, SH2, pseudokinase, and kinase (Yamaoka et al., 2004; Fagerberg et al., 2014). Once translated, JAK1 traffics to the cell membrane where it binds its cognate intracellular receptor tails, forming the readied complex necessary for cytokine signaling. We and others have previously used a forward genetics approach to identify and characterize four families with exceedingly rare IEIs (Del Bel et al., 2017; Gruber et al., 2020; Takeichi et al., 2022; Fayand et al., 2023) that are caused by GoF variants in the JAK1 gene. In these cases, the affected individuals initially presented in infancy and experienced lifelong, treatment-refractory inflammatory disease with heterogeneous features ranging from atopic dermatitis and asthma to gastrointestinal (GI) inflammation, autoimmunity, and growth defects. The four families were found to each harbor a non-synonymous single-nucleotide variant (SNV) in the JAK1 gene, resulting in the amino acid changes A634D (CADD= 32)(Del Bel et al., 2017), S703I (CADD= 26.1)(Gruber et al., 2020), H596D (CADD= 24.1)(Takeichi et al., 2022), and C787F (CADD= 28)(Fayand et al.,
