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

Autor: Louvrier C; Sorbonne Université, Inserm, Childhood Genetic Disorders, Hôpital Armand-Trousseau, and Département de Génétique médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Armand-Trousseau, Paris, France., El Khouri E; Sorbonne Université, Inserm, Childhood Genetic Disorders, Hôpital Armand-Trousseau, Paris, France., Grall Lerosey M; Département de pédiatrie et médecine de l'adolescent, CHU-Hôpitaux de Rouen, Rouen, France., Quartier P; RAISE reference centre for rare diseases, Unité d'Immunologie-Hématologie et Rhumatologie pédiatrique, and Imagine Institute, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France., Guerrot AM; Université de Rouen Normandie, Inserm Unit U1245, and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, and Normandy Center for Genomic and Personalized Medicine, Rouen, France., Bader Meunier B; RAISE reference centre for rare diseases, Unité d'Immunologie-Hématologie et Rhumatologie pédiatrique, and Imagine Institute, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France., Chican J; Sorbonne Université, Inserm, Childhood Genetic Disorders, Hôpital Armand-Trousseau, Paris, France., Mohammad M; Sorbonne Université, Inserm, Childhood Genetic Disorders, Hôpital Armand-Trousseau, Paris, France., Assrawi E; Sorbonne Université, Inserm, Childhood Genetic Disorders, Hôpital Armand-Trousseau, Paris, France., Daskalopoulou A; Sorbonne Université, Inserm, Childhood Genetic Disorders, Hôpital Armand-Trousseau, Paris, France., Arenas Garcia A; Sorbonne Université, Inserm, Childhood Genetic Disorders, Hôpital Armand-Trousseau, Paris, France., Copin B; Département de Génétique médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Armand-Trousseau, Paris, France., Piterboth W; Département de Génétique médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Armand-Trousseau, Paris, France., Dastot Le Moal F; Département de Génétique médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Armand-Trousseau, Paris, France., Karabina SA; Sorbonne Université, Inserm, Childhood Genetic Disorders, Hôpital Armand-Trousseau, Paris, France., Amselem S; Sorbonne Université, Inserm, Childhood Genetic Disorders, Hôpital Armand-Trousseau, and Département de Génétique médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Armand-Trousseau, Paris, France., Giurgea I; Sorbonne Université, Inserm, Childhood Genetic Disorders, Hôpital Armand-Trousseau, and Département de Génétique médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Armand-Trousseau, Paris, France.
Jazyk: angličtina
Zdroj: Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2023 Mar; Vol. 75 (3), pp. 468-474. Date of Electronic Publication: 2022 Dec 28.
DOI: 10.1002/art.42354
Abstrakt: 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.
(© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
Databáze: MEDLINE
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