Division of Immunology and Allergy, the Canadian Centre for Primary Immunodeficiency, the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, the Hospital for Sick Children and the University of Toronto, Toronto, Canada.
Canada-Israel Immunodeficiency Research Alliance, Toronto, Ontario, Canada; Kaplan Medical Center, Hebrew University, Rehovot, Israel.
J Allergy Clin Immunol. 2014 Mar;133(3):807-17. doi: 10.1016/j.jaci.2013.09.032. Epub 2013 Nov 13.
Mutations in the gene for the signal transducer and activator of transcription 1, STAT1, have been shown to be associated with death at an early age due to overwhelming viral infection (complete STAT1 deficiency) or, more commonly, selective deficiencies to mycobacterial or fungal infection (typically heterozygous STAT1 mutations).
To define the molecular basis of progressive combined immunodeficiency in a group of patients with fatal infections.
We studied a group of unrelated patients who displayed an unusual progressive form of combined immunodeficiency. Whole exome sequencing assisted in confirming a common genetic defect in this group, which consisted of a heterozygous mutation of the STAT1 gene. STAT1 protein level as well as function was assessed, and a detailed evaluation of the immune system, including analysis of thymus tissue, was performed.
Patients were found to carry de novo heterozygous mutations in STAT1 encoding T385A, I294T, or C284R amino acid substitutions. STAT1 expression appeared significantly decreased as a result of these changes but not completely absent, with diminished signaling responses. This group display progressive loss in lymphocyte number and function accompanied by increasing autoimmune features as well as severe, fatal infections.
These findings show that some heterozygous aberrations of STAT1 can be associated with progressive combined immunodeficiency, quite distinct from the limited susceptibilities to infection previously reported for heterozygous STAT1 mutations. These mutations were not inherited, rather, arose de novo in each case. Accompanied by significant patient mortality, this finding suggests that this class of STAT1 mutation is ultimately fatal due to overwhelming infection.
信号转导子和转录激活子 1（STAT1）基因的突变已被证明与因病毒感染（完全 STAT1 缺乏）或更常见的分枝杆菌或真菌感染（通常为杂合 STAT1 突变）而导致的早年死亡有关。
确定一组致命感染患者中进行性联合免疫缺陷的分子基础。
我们研究了一组表现出异常进行性联合免疫缺陷的无关患者。全外显子组测序有助于证实该组存在常见的遗传缺陷，即 STAT1 基因的杂合突变。评估了 STAT1 蛋白水平和功能，并对免疫系统进行了详细评估，包括对胸腺组织的分析。
患者携带新出现的 STAT1 编码 T385A、I294T 或 C284R 氨基酸取代的杂合突变。由于这些变化，STAT1 表达明显下降，但并未完全缺失，信号转导反应减弱。该组表现为淋巴细胞数量和功能进行性丧失，伴有自身免疫特征增加以及严重、致命的感染。
这些发现表明，STAT1 的一些杂合异常可能与进行性联合免疫缺陷有关，与先前报道的杂合 STAT1 突变对感染的有限易感性明显不同。这些突变不是遗传的，而是在每种情况下均为新生突变。伴随着显著的患者死亡率，这一发现表明，由于感染严重，这类 STAT1 突变最终是致命的。
