Molecular Basis of the Motheaten Phenotype
Molecular Basis of the Motheaten Phenotype
复制标题
受害表型的分子基础
作者：
F. Tsui;H. Tsui
常染色体隐性蛾化蛋白（me）或等位基因活蛾化蛋白（mev）突变纯合子小鼠表现出一种与严重免疫缺陷和自身免疫相关的独特免疫性疾病。在过去的几年里，我们的小组已经使用了蛾的小鼠作为一个模型系统，阐明了遗传和细胞的事件，有助于正常的造血和免疫细胞功能的表达。为此，我们试图确定导致蛾表型的基因。在我们最初的研究中，我们的一般方法涉及使用消减杂交来鉴定在突变小鼠与对照小鼠中差异表达的基因，从而可能提供关于主要基因缺陷的线索。使用这种方法，我们发现，编码stefin A半胱氨酸蛋白酶抑制剂的基因在me和mev小鼠的骨髓细胞中显着过表达的正常同源动物的骨髓细胞相比。然而，motheaten突变已映射到小鼠染色体6，而stefin A基因簇定位于小鼠染色体16。因此，Stefin基因并不代表主要的基因缺陷。我们的第二个策略，旨在确定的主要基因缺陷潜在的蛾的表型，促使最近的定位蛋白酪氨酸磷酸酶基因的人类染色体12 p12-p13，一个区域包含一个大的同源性片段的区域在小鼠染色体6上的蛾的基因座已被映射。我们已经表明，异常的Hcph转录表达在我和mev骨髓细胞，这些改变的转录本的产生是由于RNA剪接缺陷引起的突变小鼠的Hcph基因中的单碱基对的变化。因此，这些突变小鼠提供了一个有价值的模型系统，用于阐明HCP在体内的生物学作用，并确定造血细胞磷酸酶功能缺陷导致严重免疫缺陷和系统性自身免疫的蛾虫表型表达的机制。
Mice homozygous for the autosomal recessive motheaten (me) or the allelic viable motheaten (mev) mutations manifest a unique immunological disease associated with severe immunodeficiency and autoimmunity. Over the past few years, our group has used the motheaten mouse as a model system for elucidating the genetic and cellular events that contribute to expression of normal hematopoietic and immune cell function. To this end, we have sought to identify the gene responsible for the motheaten phenotype. In our initial studies, our general approach involved the use of subtractive hybridization to identify genes that were differentially expressed in the mutant versus control mice and which might thus provide clues as to the primary gene defect. Using this approach, we showed that genes encoding stefin A cysteine proteinase inhibitors are markedly overexpressed in bone marrow cells of me and mev mice compared to bone marrow cells of normal congenic animals. However, the motheaten mutation has been mapped to mouse choromosome 6 while the stefin A gene cluster was localized to mouse chromosome 16. Stefin gene therefore does not represent the primary gene defect. Our second strategy aimed at identifying the primary gene defect underlying the motheaten phenotype was prompted by the recent localization of a protein tyrosine phosphatase gene to human chromosome 12p12-p13, a region containing a large segment of homology with the region on mouse chromosome 6 where the motheaten locus has been mapped. We have shown that abnormal Hcph transcripts are expressed in me and mev bone marrow cells and that the generation of these altered transcripts is due to RNA splicing defects caused by single basepair changes in the Hcph genes of the mutant mice. These mutant mice thus provide a valuable model system for elucidating the biological roles of HCP in vivo and defining the mechanism whereby defective function of a hematopoietic cell phosphatase leads to expression of the motheaten phenotype of severe immunodeficiency and systemic autoimmunity.
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受害 (me/me) 和可存活的受害 (mev/mev) 突变小鼠的骨髓中淋巴细胞生成缺陷。
DOI：
--
发表时间：
1987
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Medlock,ES;Goldschneider,I;Greiner,DL;Shultz,L
通讯作者：
Shultz,L
DOI：
10.1073/pnas.89.3.1123
发表时间：
1992-02-01
影响因子：
11.1
作者：
PLUTZKY, J;NEEL, BG;ROSENBERG, RD
通讯作者：
ROSENBERG, RD
单核细胞和转化生长因子-β 对自身免疫活受害突变小鼠自然杀伤细胞分化的抑制作用。
DOI：
--
发表时间：
1991
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Koo,GC;Manyak,CL;Dasch,J;Ellingsworth,L;Shultz,LD
通讯作者：
Shultz,LD
培养物中的淋巴细胞生成通过与来自突变活受害小鼠的贴壁骨髓细胞的相互作用而被阻止。
DOI：
--
发表时间：
1988
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hayashi,S;Witte,PL;Shultz,LD;Kincade,PW
通讯作者：
Kincade,PW
DOI：
10.1172/jci114418
发表时间：
1990
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Noboru Suzuki;Tsuyoshi Sakane;E. G. Engleman
通讯作者：
Noboru Suzuki;Tsuyoshi Sakane;E. G. Engleman