Sun Jie, Hao Ziqi, Luo Hunjin, He Chufeng, Mei Lingyun, Liu Yalan, Wang Xueping, Niu Zhijie, Chen Hongsheng, Li Jia-Da, Feng Yong
Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, People's Republic of China.
Department of Otolaryngology, First Affiliated Hospital, Xinjiang Medical University, Xinjiang, People's Republic of China.
J Hum Genet. 2017 Jul;62(7):703-709. doi: 10.1038/jhg.2017.30. Epub 2017 Mar 30.
Waardenburg syndrome (WS) is an autosomal dominant inherited neurogenic disorder with the combination of various degrees of sensorineural deafness and pigmentary abnormalities affecting the skin, hair and eye. The four subtypes of WS were defined on the basis of the presence or absence of additional symptoms. Mutation of human microphthalmia-associated transcription factor (MITF) gene gives rise to WS2. Here, we identified a novel WS-associated mutation at the stop codon of MITF (p.X420Y) in a Chinese WS2 patient. This mutation resulted in an extension of extra 33 amino-acid residues in MITF. The mutant MITF appeared in both the nucleus and the cytoplasm, whereas the wild-type MITF was localized in the nucleus exclusively. The mutation led to a reduction in the transcriptional activities, whereas the DNA-binding activity was not altered. We show that the foremost mechanism was haploinsufficiency for the mild phenotypes of WS2 induced in X420Y MITF.
瓦登伯革氏综合征（WS）是一种常染色体显性遗传的神经源性疾病，其特征为不同程度的感音神经性耳聋以及影响皮肤、毛发和眼睛的色素沉着异常。WS的四个亚型是根据是否存在其他症状来定义的。人类小眼相关转录因子（MITF）基因突变会导致WS2。在此，我们在中国一名WS2患者中，于MITF的终止密码子处鉴定出一个新的与WS相关的突变（p.X420Y）。该突变导致MITF额外延伸了33个氨基酸残基。突变型MITF出现在细胞核和细胞质中，而野生型MITF仅定位于细胞核。该突变导致转录活性降低，而DNA结合活性未改变。我们表明，首要机制是X420Y MITF诱导的WS2轻度表型的单倍剂量不足。
