De novo gain‐of‐function variations in LYN lead to an early onset systemic autoinflammatory disorder

International audience; Objective: To identify the molecular basis of a severe systemic autoinflammatory disorder (SAID) and define its main phenotypical features. To functionally assess the sequence variations identified in LYN, a gene encoding a non-receptor tyrosine-kinase.Methods: (i) Targeted next-generation sequencing; (ii) In vitro functional studies of Lyn phosphorylation state and of Lyn-dependent NF-κB activity after expression of recombinant Lyn isoforms carrying different sequence variations.Results: We identified a de novo LYN variation (p.Tyr508His) in a patient presenting since birth with recurrent fever, chronic urticaria, atopic dermatitis, arthralgia, increased inflammatory biomarkers and elevated plasma cytokine levels. We studied the consequences on Lyn phosphorylation state of the Tyr508His variation and of the two LYN variations reported so far (p.Tyr508Phe and p.Tyr508*), and showed that all three variations prevent phosphorylation of residue 508 and lead to autophosphorylation of Tyr397. Additionally, these three LYN variations activate the NF-κB pathway. These results reflect a gain-of-function effect of the variations involving Tyr508 on Lyn activity.Conclusions: This study, which demonstrates the pathogenicity of the first three LYN variations identified in SAID patients, delineates the phenotypic spectrum of a disease entity characterized by an early onset severe inflammatory disease affecting neonates with no family history of SAID. All three variations affect the same tyrosine residue located in the C-terminus of Lyn, thereby underlining the critical role of this residue in the proper regulation of Lyn activity in humans.