A homozygous Fas ligand gene mutation in a patient causes a new type of autoirnmune lymphoproliferative syndrome
A homozygous Fas ligand gene mutation in a patient causes a new type of autoirnmune lymphoproliferative syndrome
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DOI：
10.1182/blood-2006-04-015776
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发表时间：
2006-08-15
期刊：
影响因子：
20.3
通讯作者：
Allende, Luis M.
中科院分区：
文献类型：
--
作者：
Del-Rey, Manuel;Ruiz-Contreras, Jesus;Allende, Luis M.
自身免疫性淋巴组织增生综合征（ALPS）是一种以淋巴组织增生和自身免疫性临床表现为特征的疾病，通常由Fas介导的凋亡缺陷引起。本报告描述了第一个纯合子FASL基因突变的妇女与临床和免疫学特征的ALPS。患者的T细胞母细胞未诱导Fas转染的小鼠L1210或Jurkat细胞上的FasL介导的细胞凋亡，并且活化诱导的细胞死亡受损。此外，Fas依赖的细胞毒性显着降低COS细胞转染突变体FasL。此外，患者T细胞母细胞上的FasL表达与健康对照中观察到的相似，尽管其在FASL启动子中具有高生产基因型-844C/C。患者的FASL基因测序显示外显子4（A247 E）的新突变。A247 E在FasL胞外区的位置以及该区域蛋白质序列在8种不同物种中的保守性支持FasL COOH末端结构域在Fas/ FasL结合中的重要作用。这些发现提供了证据，遗传性非致死性FASL异常导致一种罕见的细胞凋亡缺陷产生淋巴组织增生性疾病，他们强调需要审查目前的ALPS分类，包括一个新的ALPS Ic型亚组。
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lympho-proliferation and autoimmune clinical manifestations and is generally caused by defective Fas-mediated apoptosis. This report describes the first homozygous FASL gene mutation in a woman with clinical and immunologic features of ALPS. T-cell blasts from the patient did not induce FasL-mediated apoptosis on Fas-transfected murine L1210 or on Jurkat cells, and activation-induced cell death was impaired. Furthermore, Fas-dependent cytotoxicity was drastically reduced in COS cells transfected with the mutant FasL. In addition, FasL expression on T-cell blasts from the patient was similar to that observed in a healthy control, despite its bearing the high-producer genotype -844C/C in the FASL promoter. Sequencing of the patient's FASL gene revealed a new mutation in exon 4 (A247E). The location of A247E in the FasL extracellular domain and the conservation of the protein sequence of that region recorded in 8 species different from humans support the essential role of FasL COOH terminal domain in Fas/ FasL binding. These findings provide evidence that inherited nonlethal FASL abnormalities cause an uncommon apoptosis defect producing lymphoproliferative disease, and they highlight the need for a review of the current ALPS classification to include a new ALPS type Ic subgroup.