Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)
Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)
复制标题
腺苷脱氨酶 2 (DADA2) 缺乏症疾病表型的基因型和功能相关性
DOI：
10.1016/j.jaci.2019.12908
复制
发表时间：
2020-06-01
影响因子：
14.2
通讯作者：
Zhou, Qing
中科院分区：
文献类型：
--
作者：
Lee, Pui Y.;Kellner, Erinn S.;Zhou, Qing
背景：腺苷脱氨酶2（DADA 2）缺乏是一种以血管炎和血液系统损害为多效表现的综合征。腺苷脱氨酶2（ADA 2）突变和临床phenotype.Objective之间的关系的系统定义：我们试图测试是否影响ADA 2突变酶功能与临床presentation.Methods：患者与严重的血液学表现与血管炎为主的患者进行了比较。酶活性进行了评估，使用表达结构，反映所有53个错义，无义，插入和缺失的基因型，从152例患者在DADA 2 spectrum.Results：我们确定了患者DADA 2提出纯红细胞再生障碍性贫血（n = 5）或骨髓衰竭（BMF，n = 10）综合征。大多数患者没有表现出血管炎的特征。复发性感染、肝脾肿大和牙龈炎在BMF患者中很常见，其中一半死于感染。与伴有血管炎的DADA 2患者不同，患有纯红细胞再生障碍性贫血和BMF的患者被证明在很大程度上对TNF抑制剂无效。与血管炎相关的ADA 2变体主要反映了具有至少3%残留酶活性的错义突变。相比之下，纯红细胞再生障碍性贫血和BMF与错义突变，最小的残留酶活性，无义变体，插入/缺失导致完全lossoffunction.Conclusions：功能询问ADA 2突变揭示了一个协会的次全功能丧失与血管炎，通常响应TNF阻断，而更广泛的损失是在血液病，这可能是难治性的治疗观察。这些发现建立了DADA 2的基因型-表型谱。
Background: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable.Objective: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation.Methods: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum.Results: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function.Conclusions: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.