Poltorak A, He X, Smirnova I, Liu M Y, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B
Howard Hughes Medical Institute and the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75235-9050, USA.
Science. 1998 Dec 11;282(5396):2085-8. doi: 10.1126/science.282.5396.2085.
Mutations of the gene Lps selectively impede lipopolysaccharide (LPS) signal transduction in C3H/HeJ and C57BL/10ScCr mice, rendering them resistant to endotoxin yet highly susceptible to Gram-negative infection. The codominant Lpsd allele of C3H/HeJ mice was shown to correspond to a missense mutation in the third exon of the Toll-like receptor-4 gene (Tlr4), predicted to replace proline with histidine at position 712 of the polypeptide chain. C57BL/10ScCr mice are homozygous for a null mutation of Tlr4. Thus, the mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane. Destructive mutations of Tlr4 predispose to the development of Gram-negative sepsis, leaving most aspects of immune function intact.
Lps基因的突变选择性地阻碍了C3H/HeJ和C57BL/10ScCr小鼠体内的脂多糖（LPS）信号转导，使它们对内毒素具有抗性，但对革兰氏阴性菌感染高度敏感。已证明C3H/HeJ小鼠的共显性Lpsd等位基因对应于Toll样受体4基因（Tlr4）第三外显子中的一个错义突变，预计该突变会使多肽链第712位的脯氨酸被组氨酸取代。C57BL/10ScCr小鼠是Tlr4无效突变的纯合子。因此，哺乳动物的Tlr4蛋白主要用于识别LPS，并可能将LPS信号跨质膜进行转导。Tlr4的破坏性突变易导致革兰氏阴性菌败血症的发生，而免疫功能的大多数方面仍保持完整。
