De Novo Gain‐Of‐Function Variations in LYN Associated With an Early‐Onset Systemic Autoinflammatory Disorder

Abstract

Objective To identify the molecular basis of a severe systemic autoinflammatory disorder (SAID) and define its main phenotypic features, and to functionally assess the sequence variations identified in LYN, a gene encoding a nonreceptor tyrosine kinase. Methods We used targeted next‐generation sequencing and in vitro functional studies of Lyn phosphorylation state and 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 p.Tyr508His variation and of the 2 LYN variations reported so far (p.Tyr508Phe and p.Tyr508*), and found that all 3 variations prevent phosphorylation of residue 508 and lead to autophosphorylation of Tyr397. Additionally, these 3 LYN variations activate the NF‐κB pathway. These results show a gain‐of‐function effect of the variations involving Tyr508 on Lyn activity. Conclusion This study demonstrates the pathogenicity of the first 3 LYN variations identified in SAID patients and delineates the phenotypic spectrum of a disease entity characterized by severe, early‐onset, systemic inflammatory disease affecting neonates with no family history of SAID. All 3 LYN variations affect the same tyrosine residue located in the C‐terminus of Lyn, thereby demonstrating the critical role of this residue in the proper regulation of Lyn activity in humans.

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

“…Instead, GOF mutations in HCK and LYN present with perinatalonset systemic inflammation, neutrophilic small vessel (or leukocytoclastic) vasculitis, and lung inflammation with a HCK GOF mutation 10 and liver fibrosis with LYN GOF, respectively. A recent case report of a 3-year-old girl with a LYN missense mutation, p.Y508H, who presents with urticarial rash and systemic inflammation is largely consistent with the LAVLI phenotype described 39 . However, the findings of dysmorphic features and developmental delay that are described in that patient point to potential involvement of additional genetic factors.…”

Myeloid Src-family kinases are critical for neutrophil-mediated autoinflammation in gout and motheaten models

“…A recent paper has also identified gain-of-function mutations in Syk as the likely causative agent of systemic inflammation in human patients and in mice carrying the most severe human mutation ( Wang et al, 2021 ). In addition, gain-of function mutations in Hck ( Kanderova et al, 2022 ; Ernst et al, 2002 ), Fgr ( Abe et al, 2019 ), or Lyn ( Louvrier et al, 2023 ; de Jesus et al, 2023 ; Hibbs et al, 2002 ) cause spontaneous inflammation in pediatric patients or experimental mice. We have also previously shown that the severe early inflammatory reactions of the motheaten mice are caused by SHP-1 deletion in the neutrophil lineage, likely due to excessive activation of tyrosine phosphorylation pathways in those cells ( Abram et al, 2013 ).…”

Update on autoinflammatory diseases

“…Following the discovery of genes mutated in FMF and TRAPS genes (MEFV and TNFRSF1A) [1,29], there are now more than 50 monogenic SAIDs. A new disease is described almost every month [30,31,32 ▪ ,33 ▪ ].…”