Genomic, transcriptional and mutational analysis of the mouse microphthalmia locus.
Genomic, transcriptional and mutational analysis of the mouse microphthalmia locus.
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发表时间：
2000-05
期刊：
影响因子：
3.3
通讯作者：
Jón Hallsteinn Hallsson;J. Favor;C. Hodgkinson;T. Glaser;M. Lamoreux;R. Magnúsdóttir;G. J. Gunnarsson;H. Sweet;N. Copeland;N. Jenkins;E. Steingrímsson
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作者：
Jón Hallsteinn Hallsson;J. Favor;C. Hodgkinson;T. Glaser;M. Lamoreux;R. Magnúsdóttir;G. J. Gunnarsson;H. Sweet;N. Copeland;N. Jenkins;E. Steingrímsson
小鼠小眼炎转录因子(MITF)突变影响四种细胞类型的发育：黑素细胞、肥大细胞、破骨细胞和眼睛的色素上皮细胞。这些突变是表型多样的，可以按等位基因序列排列。在人类中，MITF突变会导致2A型Waardenburg综合征(WS2A)和Tietz综合征，这两种常染色体显性疾病会导致耳聋和色素减退。因此，MITF小鼠是研究人类疾病的一个重要的模型系统。在这里，我们报道了小鼠MITF基因的完整外显子/内含子结构，并表明它与人类基因相似。我们还发现，小鼠的基因在转录上是复杂的，能够产生至少13种不同的MITF亚型。这些异构体中的一些缺失了蛋白质的重要功能结构域，提示它们可能在MITF功能和信号转导中发挥抑制作用。此外，我们还确定了六个小眼球突变的分子基础。其中两个突变是首次报道的(MITF(mi-enu198)和MITF(mi-x39))，其他突变(MITF(mi-ws)、MITF(mi-bws)、MITF(mi-ew)和MITF(mi-di))已被描述，但突变的分子基础尚未确定。根据这里提供的基因组和转录数据进行分析，很明显，这些突变是由于RNA加工或转录缺陷造成的。有趣的是，其中三个突变(MITF(mi-x39)、MITF(mi-bws)和MITF(mi-ws))产生的蛋白质缺少体外研究中确定的蛋白质的重要功能域，进一步证实了这些域在整个动物中的生物学作用。
Mouse microphthalmia transcription factor (Mitf) mutations affect the development of four cell types: melanocytes, mast cells, osteoclasts, and pigmented epithelial cells of the eye. The mutations are phenotypically diverse and can be arranged in an allelic series. In humans, MITF mutations cause Waardenburg syndrome type 2A (WS2A) and Tietz syndrome, autosomal dominant disorders resulting in deafness and hypopigmentation. Mitf mice thus represent an important model system for the study of human disease. Here we report the complete exon/intron structure of the mouse Mitf gene and show it to be similar to the human gene. We also found that the mouse gene is transcriptionally complex and is capable of generating at least 13 different Mitf isoforms. Some of these isoforms are missing important functional domains of the protein, suggesting that they might play an inhibitory role in Mitf function and signal transduction. In addition, we determined the molecular basis for six microphthalmia mutations. Two of the mutations are reported for the first time here (Mitf(mi-enu198) and Mitf(mi-x39)), while the others (Mitf(mi-ws), Mitf(mi-bws), Mitf(mi-ew), and Mitf(mi-di)) have been described but the molecular basis for the mutation not determined. When analyzed in terms of the genomic and transcriptional data presented here, it is apparent that these mutations result from RNA processing or transcriptional defects. Interestingly, three of the mutations (Mitf(mi-x39), Mitf(mi-bws), and Mitf(mi-ws)) produce proteins that are missing important functional domains of the protein identified in in vitro studies, further confirming a biological role for these domains in the whole animal.