Department of Otolaryngology Head and Neck Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
Province Key Laboratory of Otolaryngology Critical Disease, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
J Hum Genet. 2018 May;63(5):639-646. doi: 10.1038/s10038-018-0425-z. Epub 2018 Mar 12.
Mutation in the gene encoding microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome 2 (WS2), an autosomal dominantly inherited syndrome with auditory-pigmentary abnormalities, which is clinically and genetically heterogeneous. Haploinsufficiency may be the underlying mechanism for WS2. However, the mechanisms explaining the genotypic and phenotypic variations in WS2 caused by MITF mutations are unclear. A previous study revealed that MITF interacts with LEF-1, an important factor in the Wnt signaling pathway, to regulate its own transcription through LEF-1-binding sites on the MITF promoter. In this study, four different WS2-associated MITF mutations (p.R217I, p.R217G, p.R255X, p.R217del) that are associated with highly variable clinical features were chosen. According to the results, LEF-1 can activate the expression of MITF on its own, but MITF proteins inhibited the activation. This inhibition weakens when the dosage of MITF is reduced. Except for p.R217I, p.R255X, p.R217G, and p.R217del lose the ability to activate TYR completely and do not inhibit the LEF-1-mediated activation of the MITF-M promoter, and the haploinsufficiency created by mutant MITF can be overcome; correspondingly, the mutants' associated phenotypes are less severe than that of p.R217I. The dominant negative of p.R217del made it have a second-most severe phenotype. This study's data imply that MITF has a negative feedback loop of regulation to stabilize MITF gene dosage that involves the Wnt signaling pathway and that the interaction of MITF mutants with this pathway drives the genotypic and phenotypic differences observed in Waardenburg syndrome type 2 associated with MITF mutations.
MITF 基因（编码小眼畸形相关转录因子）突变导致 Waardenburg 综合征 2 型（WS2），这是一种常染色体显性遗传综合征，具有听觉-色素异常，临床上和遗传上具有异质性。MITF 基因的单倍不足可能是 WS2 的潜在机制。然而，MITF 基因突变导致 WS2 的基因型和表型变异的机制尚不清楚。先前的一项研究表明，MITF 与 LEF-1（Wnt 信号通路的重要因子）相互作用，通过 MITF 启动子上的 LEF-1 结合位点来调节自身转录。在这项研究中，选择了四个与高度可变临床特征相关的不同 WS2 相关 MITF 突变（p.R217I、p.R217G、p.R255X、p.R217del）。结果表明，LEF-1 可以独立激活 MITF 的表达，但 MITF 蛋白抑制了激活。当 MITF 的剂量减少时，这种抑制作用会减弱。除了 p.R217I，p.R255X、p.R217G 和 p.R217del 完全丧失了激活 TYR 的能力，并且不能抑制 LEF-1 介导的 MITF-M 启动子的激活，突变 MITF 造成的单倍不足可以被克服；相应地，突变相关的表型比 p.R217I 更轻。p.R217del 的显性负性使其具有第二严重的表型。本研究的数据表明，MITF 具有涉及 Wnt 信号通路的基因剂量的负反馈调节机制，MITF 突变体与该通路的相互作用导致了与 MITF 突变相关的 Waardenburg 综合征 2 型的基因型和表型差异。
