Rao E, Blaschke R J, Marchini A, Niesler B, Burnett M, Rappold G A
Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
Hum Mol Genet. 2001 Dec 15;10(26):3083-91. doi: 10.1093/hmg/10.26.3083.
Functional impairment of the human homeobox gene SHOX causes short stature and Madelung deformity in Leri-Weill syndrome (LWS) and has recently been implicated in additional skeletal malformations frequently observed in Turner syndrome. To enhance our understanding of the underlying mechanism of action, we have established a cell culture model consisting of four stably transfected cell lines and analysed the functional properties of the SHOX protein on a molecular level. Results show that the SHOX-encoded protein is located exclusively within the nucleus of a variety of cell lines, including U2Os, HEK293, COS7 and NIH 3T3 cells. In contrast to this cell-type independent nuclear translocation, the transactivating potential of the SHOX protein on different luciferase reporter constructs was observed only in the osteogenic cell line U2Os. Since C-terminally truncated forms of SHOX lead to LWS and idiopathic short stature, we have compared the activity of wild-type and truncated SHOX proteins. Interestingly, C-terminally truncated SHOX proteins are inactive with regards to target gene activation. These results for the first time provide an explanation of SHOX-related phenotypes on a molecular level and suggest the existence of qualitative trait loci modulating SHOX activity in a cell-type specific manner.
人类同源框基因SHOX的功能缺陷会导致Leri-Weill综合征（LWS）患者身材矮小和马德隆畸形，最近还发现其与特纳综合征中常见的其他骨骼畸形有关。为了增进我们对其潜在作用机制的理解，我们建立了一个由四个稳定转染细胞系组成的细胞培养模型，并在分子水平上分析了SHOX蛋白的功能特性。结果表明，SHOX编码的蛋白仅定位于多种细胞系的细胞核内，包括U2Os、HEK293、COS7和NIH 3T3细胞。与这种不依赖细胞类型的核转位不同，仅在成骨细胞系U2Os中观察到SHOX蛋白对不同荧光素酶报告基因构建体的反式激活潜力。由于SHOX的C末端截短形式会导致LWS和特发性身材矮小，我们比较了野生型和截短型SHOX蛋白的活性。有趣的是，C末端截短的SHOX蛋白在靶基因激活方面无活性。这些结果首次在分子水平上解释了与SHOX相关的表型，并表明存在以细胞类型特异性方式调节SHOX活性的质量性状基因座。
