Tsui F W, Tsui H W
Arthritis Centre Research Unit, Toronto Hospital Research Institute, Canada.
Immunol Rev. 1994 Apr;138:185-206. doi: 10.1111/j.1600-065x.1994.tb00852.x.
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.
纯合子常染色体隐性突变型motheaten（me）或等位基因存活型motheaten（mev）的小鼠表现出一种独特的免疫疾病，伴有严重的免疫缺陷和自身免疫。在过去几年中，我们的研究小组将motheaten小鼠用作模型系统，以阐明有助于正常造血和免疫细胞功能表达的遗传和细胞事件。为此，我们试图鉴定导致motheaten表型的基因。在我们最初的研究中，我们的一般方法是利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，这些基因可能因此提供有关主要基因缺陷的线索。通过这种方法，我们发现与正常同基因动物的骨髓细胞相比，编码stefin A半胱氨酸蛋白酶抑制剂的基因在me和mev小鼠的骨髓细胞中明显过度表达。然而，motheaten突变已定位到小鼠6号染色体，而stefin A基因簇位于小鼠16号染色体。因此，stefin基因并不代表主要基因缺陷。我们旨在鉴定motheaten表型潜在主要基因缺陷的第二种策略，是由最近将一个蛋白酪氨酸磷酸酶基因定位到人类12号染色体p12 - p13区域所引发的，该区域与小鼠6号染色体上已定位motheaten位点的区域有很大一段同源性。我们已经表明，异常的Hcph转录本在me和mev骨髓细胞中表达，并且这些改变的转录本的产生是由于突变小鼠Hcph基因中的单碱基对变化导致的RNA剪接缺陷。因此，这些突变小鼠为阐明HCP在体内的生物学作用以及确定造血细胞磷酸酶功能缺陷导致严重免疫缺陷和全身性自身免疫的motheaten表型表达的机制提供了一个有价值的模型系统。
