Watanabe A, Takeda K, Ploplis B, Tachibana M
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA.
Nat Genet. 1998 Mar;18(3):283-6. doi: 10.1038/ng0398-283.
Waardenburg syndrome (WS) is a hereditary disorder that causes hypopigmentation and hearing impairment. Depending on additional symptoms, WS is classified into four types: WS1, WS2, WS3 and WS4. Mutations in MITF (microphthalmia-associated transcription factor) and PAX3, encoding transcription factors, are responsible for WS2 and WS1/WS3, respectively. We have previously shown that MITF transactivates the gene for tyrosinase, a key enzyme for melanogenesis, and is critically involved in melanocyte differentiation. Absence of melanocytes affects pigmentation in the skin, hair and eyes, and hearing function in the cochlea. Therefore, hypopigmentation and hearing loss in WS2 are likely to be the results of an anomaly of melanocyte differentiation caused by MITF mutations. However, the molecular mechanism by which PAX3 mutations cause the auditory-pigmentary symptoms in WS1/WS3 remains to be explained. Here we show that PAX3, a transcription factor with a paired domain and a homeodomain, transactivates the MITF promoter. We further show that PAX3 proteins associated with WS1 in either the paired domain or the homeodomain fail to recognize and transactivate the MITF promoter. These results provide evidence that PAX3 directly regulates MITF and suggest that the failure of this regulation due to PAX3 mutations causes the auditory-pigmentary symptoms in at least some individuals with WS1.
瓦登伯革氏综合征（WS）是一种遗传性疾病，可导致色素减退和听力障碍。根据其他症状，WS可分为四种类型：WS1、WS2、WS3和WS4。小眼相关转录因子（MITF）和编码转录因子的PAX3中的突变分别导致WS2和WS1/WS3。我们之前已经表明，MITF可反式激活酪氨酸酶基因，酪氨酸酶是黑色素生成的关键酶，并且在黑素细胞分化中起关键作用。黑素细胞的缺失会影响皮肤、头发和眼睛的色素沉着以及耳蜗的听力功能。因此，WS2中的色素减退和听力丧失可能是由MITF突变导致的黑素细胞分化异常的结果。然而，PAX3突变导致WS1/WS3中听觉色素沉着症状的分子机制仍有待解释。在这里，我们表明，具有配对结构域和同源结构域的转录因子PAX3可反式激活MITF启动子。我们进一步表明，在配对结构域或同源结构域中与WS1相关的PAX3蛋白无法识别和反式激活MITF启动子。这些结果提供了PAX3直接调节MITF的证据，并表明由于PAX3突变导致的这种调节失败在至少一些WS1个体中引起了听觉色素沉着症状。
