De Novo Gain-Of-Function Variations in LYN Associated With an Early-Onset Systemic Autoinflammatory Disorder
De Novo Gain-Of-Function Variations in LYN Associated With an Early-Onset Systemic Autoinflammatory Disorder
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DOI：
10.1002/art.42354
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发表时间：
2022-12-28
影响因子：
13.3
通讯作者：
Giurgea, Irina
中科院分区：
文献类型：
--
作者：
Louvrier, Camille;El Khouri, Elma;Giurgea, Irina
Objective.确定严重系统性自身炎症性疾病（SAID）的分子基础，确定其主要表型特征，并对编码非受体酪氨酸激酶的基因林恩中鉴定的序列变异进行功能评估。方法.我们使用靶向下一代测序和体外功能研究表达携带不同序列变异的重组林恩同种型后的林恩磷酸化状态和Lyn依赖性NF-κ B活性。结果我们在一名出生后出现反复发热、慢性荨麻疹、特应性皮炎、关节痛、炎症生物标志物增加和血浆细胞因子水平升高的患者中发现了一种新发林恩变异（p.Tyr508 His）。我们研究了p.Tyr508 His变异和迄今报道的2种林恩变异（p.Tyr508 Phe和p.Tyr508*）对林恩磷酸化状态的影响，发现所有3种变异均阻止残基508的磷酸化并导致Tyr 397的自磷酸化。此外，这3种林恩变异激活NF-κ B通路。这些结果显示了涉及Tyr 508的变化对林恩活性的功能获得效应。结论本研究证实了在SAID患者中鉴定的前3个林恩变异的致病性，并描绘了以影响无SAID家族史的新生儿的严重、早发性、全身性炎症性疾病为特征的疾病实体的表型谱。所有3种林恩变异均影响位于林恩C-末端的相同酪氨酸残基，从而证明该残基在人类林恩活性的适当调节中的关键作用。
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-kappa B 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-kappa B 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.