MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function
MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function
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DOI：
10.1093/hmg/ddt285
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发表时间：
2013-11-01
影响因子：
3.5
通讯作者：
Steingrimsson, Eirikur
中科院分区：
文献类型：
--
作者：
Grill, Christine;Bergsteinsdottir, Kristin;Steingrimsson, Eirikur
碱性螺旋-环螺旋-亮氨酸拉链（bHLHZip）蛋白MITF（小眼症相关转录因子）是黑素细胞发育的主要调节因子。在显性遗传性色素减退和耳聋综合征Waardenburg综合征2A型（WS 2A）和Tietz综合征（TS）患者中发现了MITF突变。此外，在黑色素瘤患者的MITF中发现了体细胞和生殖细胞突变。在这里，我们的特点的DNA结合和转录激活特性的24 MITF突变发现WS 2A，TS和黑色素瘤患者。我们发现，大多数WS 2A和TS突变不能结合DNA和激活黑素细胞特异性启动子的表达。一些突变，特别是R203 K和S298 P，表现出正常的活性，可能代表中性变体。在黑色素瘤中发现的突变显示出正常的DNA结合和转录激活特性的微小变化;一些显示出形成集落的潜力增加。我们的研究结果为单个基因的突变如何导致如此不同的表型提供了分子见解。
The basic-helixloophelix-leucine zipper (bHLHZip) protein MITF (microphthalmia-associated transcription factor) is a master regulator of melanocyte development. Mutations in the MITF have been found in patients with the dominantly inherited hypopigmentation and deafness syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS). Additionally, both somatic and germline mutations have been found in MITF in melanoma patients. Here, we characterize the DNA-binding and transcription activation properties of 24 MITF mutations found in WS2A, TS and melanoma patients. We show that most of the WS2A and TS mutations fail to bind DNA and activate expression from melanocyte-specific promoters. Some of the mutations, especially R203K and S298P, exhibit normal activity and may represent neutral variants. Mutations found in melanomas showed normal DNA-binding and minor variations in transcription activation properties; some showed increased potential to form colonies. Our results provide molecular insights into how mutations in a single gene can lead to such different phenotypes.