Background

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.

Objective

We describe 2 siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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自身免疫性淋巴增生综合征样疾病中的RASGRP1突变

背景

自身免疫性淋巴组织增生综合症（ALPS）是由于凋亡受损而引起的淋巴细胞稳态的遗传性疾病。它最初被认为是一种非常罕见的疾病，但是最近的研究表明，它可能比以前认为的更为普遍。已在一部分ALPS患者中鉴定出几个基因的缺陷，但其中约三分之一的患者在遗传上仍不确定。

客观的

我们描述了呈现ALPS样疾病的2个兄弟姐妹。这项研究旨在确定导致该表型的遗传原因。

方法

全外显子组测序以及分子和功能分析用于鉴定和表征遗传缺陷。还进行了临床和免疫分析，并进行了报告。

结果

2例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，并存在抗核自身抗体和其他自身抗体，但双阴性T细胞正常。他们还遭受反复感染。在这两个兄弟姐妹中鉴定出了编码Ras鸟苷酸核苷酸释放蛋白1的RASGRP1的新型复合杂合突变。突变削弱了T细胞受体信号传导，导致缺陷的T细胞活化和增殖，以及活化诱导的T细胞细胞死亡受损。

结论

这项研究首次表明在ALPS样疾病患者中应考虑RASGRP1突变。我们还建议调查相似患者但遗传原因未知的T细胞受体信号通路中涉及的细胞内蛋白。