Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, Gatta L B, Ochs H D, Schwarz K, Notarangelo L D, Vezzoni P, Spanopoulou E
Department of Human Genome and Multifactorial Disease, Istituto di Tecnologie Biomediche Avanzate, Consiglio Nazionale delle Ricerche, Segrate (Milano) Italy.
Cell. 1998 May 29;93(5):885-96. doi: 10.1016/s0092-8674(00)81448-8.
Genomic rearrangement of the antigen receptor loci is initiated by the two lymphoid-specific proteins Rag-1 and Rag-2. Null mutations in either of the two proteins abrogate initiation of V(D)J recombination and cause severe combined immunodeficiency with complete absence of mature B and T lymphocytes. We report here that patients with Omenn syndrome, a severe immunodeficiency characterized by the presence of activated, anergic, oligoclonal T cells, hypereosinophilia, and high IgE levels, bear missense mutations in either the Rag-1 or Rag-2 genes that result in partial activity of the two proteins. Two of the amino acid substitutions map within the Rag-1 homeodomain and decrease DNA binding activity, while three others lower the efficiency of Rag-1/Rag-2 interaction. These findings provide evidence to indicate that the immunodeficiency manifested in patients with Omenn syndrome arises from mutations that decrease the efficiency of V(D)J recombination.
抗原受体基因座的基因组重排由两种淋巴细胞特异性蛋白Rag-1和Rag-2启动。这两种蛋白中任何一种的无效突变都会消除V(D)J重组的起始，并导致严重联合免疫缺陷，完全缺乏成熟的B淋巴细胞和T淋巴细胞。我们在此报告，患有奥门综合征的患者，这是一种严重免疫缺陷疾病，其特征为存在活化的、无反应性的寡克隆T细胞、嗜酸性粒细胞增多和高IgE水平，在Rag-1或Rag-2基因中携带错义突变，导致这两种蛋白具有部分活性。其中两个氨基酸替换位于Rag-1同源结构域内，降低了DNA结合活性，而另外三个则降低了Rag-1/Rag-2相互作用的效率。这些发现提供了证据，表明奥门综合征患者表现出的免疫缺陷源于降低V(D)J重组效率的突变。
