Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity
Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity
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DOI：
10.1056/nejm199611283352204
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发表时间：
1996-11-28
影响因子：
158.5
通讯作者：
Elkon, KB
中科院分区：
文献类型：
--
作者：
Drappa, J;Vaishnaw, AK;Elkon, KB
背景 Canale-Smith 综合征是一种以淋巴结病和自身免疫为特征的儿童疾病。该综合征与具有淋巴细胞增殖 (lpr) 表型或全身性淋巴增殖性疾病 (gld) 表型的小鼠之间的相似性促使我们研究它是否也是由调节淋巴细胞凋亡的 Fas 基因（lpr 小鼠）或 Fas 配体（gld 小鼠）突变引起的。方法我们研究了四名患有该综合征的患者及其家人。分析 T 淋巴细胞表型，并测定活化 T 细胞对 Fas 介导的体外凋亡的敏感性。通过核苷酸序列分析寻找 Fas 突变。 结果 Canale-Smith 综合征患者的循环双阴性 T 细胞数量增加（>20%），并且与抗 Fas 抗体一起孵育的活化 T 细胞的凋亡严重受损。鉴定出三种新的 Fas 突变，所有突变都是杂合的，预计会损害 Fas 的信号转导。该疾病的自身免疫表现，例如溶血性贫血和血小板减少症，持续到青春期。两名患者进入成年后出现间歇性淋巴结肿大，但随着时间的推移逐渐减轻。两人均出现了肿瘤，其中一人在 43 岁时死于肝细胞癌。 结论 Canale-Smith 综合征患者的 Fas 存在突变，这一事实表明该基因与淋巴细胞的积累和该综合征的自身免疫特征有关。 (C)1996，马萨诸塞州医学会。
Background The Canale-Smith syndrome is a childhood disorder characterized by lymphadenopathy and autoimmunity. The similarity between this syndrome and that in mice with the lymphoproliferation (lpr) phenotype or the generalized-lymphoproliferative-disease (gld) phenotype led us to investigate whether it too is caused by mutations of the Fas gene (lpr mice) or the Fas ligand (gld mice), which regulate apoptosis in lymphocytes.Methods We studied four patients with the syndrome and their families. T-lymphocyte phenotypes were analyzed, and the susceptibility of activated T cells to Fas-mediated apoptosis in vitro was determined. Mutations of Fas were sought by nucleotide-sequence analysis.Results Patients with the Canale-Smith syndrome had increased numbers of circulating double-negative T cells (>20 percent) and profoundly impaired apoptosis of activated T cells incubated with an anti-Fas antibody. Three novel Fas mutations were identified, all of which were heterozygous and predicted to impair signal transduction by Fas. Autoimmune manifestations of the disease, such as hemolytic anemia and thrombocytopenia, persisted into adolescence. Two patients followed into adulthood had intermittent lymphadenopathy, which diminished over time. Neoplasms developed in both, and one died of hepatocellular carcinoma at the age of 43.Conclusions Patients with the Canale-Smith syndrome have mutations in Fas - a fact that implicates this gene in the accumulation of lymphocytes and the autoimmunity characteristic of the syndrome. (C)1996, Massachusetts Medical Society.