Department of Paediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China; Shenzhen Engineering Laboratory of Primary Immunodeficiency Diagnosis and Therapy, Shenzhen, China.
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China; Shenzhen Engineering Laboratory of Primary Immunodeficiency Diagnosis and Therapy, Shenzhen, China.
J Allergy Clin Immunol. 2018 Aug;142(2):595-604.e16. doi: 10.1016/j.jaci.2017.10.026. Epub 2017 Nov 15.
Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to impaired apoptosis. It was initially regarded as a very rare disease, but recent studies show that it may be more common than previously thought. Defects in a couple of genes have been identified in a proportion of patients with ALPS, but around one-third of such patients remain undefined genetically.
We describe 2 siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype.
Whole-exome sequencing and molecular and functional analyses were used to identify and characterize the genetic defect. Clinical and immunological analysis was also performed and reported.
The 2 patients presented with chronic lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, and the presence of antinuclear autoantibody and other autoantibodies, but normal double-negative T cells. They also suffered from recurrent infections. Novel compound heterozygous mutations of RASGRP1 encoding Ras guanyl nucleotide releasing protein 1 were identified in the 2 siblings. The mutations impaired T-cell receptor signaling, leading to defective T-cell activation and proliferation, as well as impaired activation-induced cell death of T cells.
This study shows for the first time that RASGRP1 mutation should be considered in patients with ALPS-like disease. We also propose to investigate the intracellular proteins involved in the T-cell receptor signaling pathway in similar patients but with unknown genetic cause.
自身免疫性淋巴增生综合征（ALPS）是一种由于细胞凋亡受损而导致淋巴细胞稳态异常的遗传性疾病。它最初被认为是一种非常罕见的疾病，但最近的研究表明，它可能比以前认为的更为常见。在一部分 ALPS 患者中已经确定了几个基因的缺陷，但仍有三分之一左右的此类患者在遗传上无法定义。
我们描述了 2 例具有 ALPS 样疾病的同胞。本研究旨在确定导致这种表型的遗传原因。
采用外显子组测序以及分子和功能分析来鉴定和描述遗传缺陷。还进行了临床和免疫学分析，并进行了报道。
这 2 名患者表现为慢性淋巴结病、肝脾肿大、自身免疫性溶血性贫血、免疫性血小板减少症，以及存在抗核自身抗体和其他自身抗体，但双阴性 T 细胞正常。他们还经常发生反复感染。在这 2 位同胞中发现了 Ras 鸟苷酸释放蛋白 1（RASGRP1）编码 Ras 鸟苷酸释放蛋白 1 的新型复合杂合突变。这些突变损害了 T 细胞受体信号转导，导致 T 细胞激活和增殖缺陷，以及 T 细胞激活诱导的细胞死亡缺陷。
这项研究首次表明，在具有 ALPS 样疾病的患者中应考虑 RASGRP1 突变。我们还建议在具有未知遗传原因的类似患者中研究参与 T 细胞受体信号通路的细胞内蛋白。
