Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II
Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II
复制标题
瓦登堡综合征相关的 PAX3 和 SOX10 突变的功能分析：瓦登堡综合征 II 型显性失活 SOX10 突变的报告
DOI：
10.1007/s00439-011-1098-2
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发表时间：
2012-03-01
期刊：
影响因子：
5.3
通讯作者：
Feng, Yong
中科院分区：
文献类型：
--
作者：
Zhang, Hua;Chen, Hongsheng;Feng, Yong
瓦登伯格综合征（WS）是一种因黑素细胞缺陷导致的听觉 - 色素障碍性疾病，表现为感音神经性听力损失与毛发、皮肤及内耳色素沉着异常的不同组合。根据其他伴随症状，WS可分为四种亚型（WS1 - WS4）。PAX3和SOX10是两种转录因子，它们能够激活小眼畸形相关转录因子（MITF）的表达，而MITF是黑素细胞发育的关键转录因子。PAX3突变与WS1和WS3相关，而SOX10突变则导致WS2和WS4。最近，我们在一组中国WS患者中发现了PAX3和SOX10的一些新的与WS相关的突变。在此，我们在一个WS2家系中进一步鉴定出SOX10的E248fsX30突变。我们分析了两个PAX3突变（p.H80D、p.H186fsX5）和四个SOX10突变（p.E248fsX30、p.G37fsX58、p.G38fsX69和p.R43X）的亚细胞分布、表达情况及体外活性。除了H80D PAX3保留部分活性外，其他突变体均无法激活MITF启动子。H80D PAX3和E248fsX30 SOX10与野生型（WT）蛋白一样定位于细胞核，而其他突变蛋白则在细胞质和细胞核中均有分布。此外，E248fsX30 SOX10蛋白保留了DNA结合活性，并对野生型SOX10表现出显性负效应。然而，E248fsX30 SOX10蛋白似乎比野生型蛋白降解得更快，这可能是该突变导致轻度WS2表型的原因。
Waardenburg syndrome (WS) is an auditory-pigmentary disorder resulting from melanocyte defects, with varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1-WS4) based on additional symptoms. PAX3 and SOX10 are two transcription factors that can activate the expression of microphthalmia-associated transcription factor (MITF), a critical transcription factor for melanocyte development. Mutations of PAX3 are associated with WS1 and WS3, while mutations of SOX10 cause WS2 and WS4. Recently, we identified some novel WS-associated mutations in PAX3 and SOX10 in a cohort of Chinese WS patients. Here, we further identified an E248fsX30 SOX10 mutation in a family of WS2. We analyzed the subcellular distribution, expression and in vitro activity of two PAX3 mutations (p.H80D, p.H186fsX5) and four SOX10 mutations (p.E248fsX30, p.G37fsX58, p.G38fsX69 and p.R43X). Except H80D PAX3, which retained partial activity, the other mutants were unable to activate MITF promoter. The H80D PAX3 and E248fsX30 SOX10 were localized in the nucleus as wild type (WT) proteins, whereas the other mutant proteins were distributed in both cytoplasm and nucleus. Furthermore, E248fsX30 SOX10 protein retained the DNA-binding activity and showed dominant-negative effect on WT SOX10. However, E248fsX30 SOX10 protein seems to decay faster than the WT one, which may underlie the mild WS2 phenotype caused by this mutation.