DEFECTIVE HUMAN INTERLEUKIN-2 RECEPTOR-GAMMA CHAIN IN AN ATYPICAL X-CHROMOSOME-LINKED SEVERE COMBINED IMMUNODEFICIENCY WITH PERIPHERAL T-CELLS
DEFECTIVE HUMAN INTERLEUKIN-2 RECEPTOR-GAMMA CHAIN IN AN ATYPICAL X-CHROMOSOME-LINKED SEVERE COMBINED IMMUNODEFICIENCY WITH PERIPHERAL T-CELLS
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DOI：
10.1073/pnas.91.20.9466
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发表时间：
1994-09-27
影响因子：
11.1
通讯作者：
DESAINTBASILE, G
中科院分区：
文献类型：
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作者：
DISANTO, JP;RIEUXLAUCAT, F;DESAINTBASILE, G
X染色体连锁的严重联合免疫缺陷病（SCIDX 1）的特征是缺乏T细胞和自然杀伤细胞的发育，并由白细胞介素2受体（IL-2 R）γ链的分子突变引起。IL-2 R γ链是IL-2、IL-4和IL-7受体系统的共同组分，这可以解释SCIDX 1中的严重免疫表型。我们以前曾描述过一种非典型的SCIDX 1综合征，表现为外周血T细胞功能低下，我们假设这代表了SCIDX 1基因座上的一个变异等位基因。我们现在证明IL-2 R γ基因中的剪接位点突变是导致这种非典型SCIDX 1的原因。异常的RNA剪接导致产生两种IL-2 R γ转录物：一种是含有小内含子插入的丰富的非功能性同种型，另一种是含有少量单个氨基酸取代的功能性同种型。放射性标记的IL-2结合研究显示功能性高亲和力IL-2 R的表达水平降低了5倍，这与全长IL-2 R γ转录物的数量相关。对患者T细胞的T细胞抗原受体β链库的进一步分析证明了多个V-β家族中的寡克隆性，因此强烈表明IL-2 R γ链中的缺陷产生了有限数量的外周T细胞克隆。这种非典型SCIDX 1患者表明，某些IL-2 R γ链异常也可能导致部分免疫缺陷表型，可能通过对IL-2，IL-4或IL-7受体系统的差异效应。
X chromosome-linked severe combined immunodeficiency disease (SCIDX1) is characterized by the absence of T-cell and natural killer cell development and results from molecular mutations of the interleukin 2 receptor (IL-2R) gamma chain. The IL-2R gamma chain is a common component of the IL-2, IL-4, and IL-7 receptor systems, which may explain the severe immunophenotype in SCIDX1. We have previously described an atypical SCIDX1 syndrome demonstrating poorly functioning peripheral T cells, which we hypothesized to represent a variant allele at the SCIDX1 locus. We now demonstrate that a splice site mutation in the IL-2R gamma gene is responsible for this atypical SCIDX1. Aberrant RNA splicing resulted in the generation of two IL-2R gamma transcripts: an abundant, nonfunctional isoform containing a small intronic insertion and a second functional isoform with a single amino acid substitution present in limited amounts. Radiolabeled IL-2 binding studies revealed a 5-fold decreased level of expression of functional high-affinity IL-2Rs, which correlated with the quantity of full-length IL-2R gamma transcripts. Further analysis of the T-cell antigen receptor beta-chain repertoire of the patient's T cells demonstrated oligoclonality in multiple V-beta families, thus strongly suggesting that the defect in the IL-2R gamma chain generated a limited number of peripheral T-cell clones. This atypical SCIDX1 patient demonstrates that certain IL-2R gamma chain abnormalities can also result in partial immunodeficiency phenotypes, potentially through differential effects on the IL-2, IL-4, or IL-7 receptor systems.