Waardenburg综合征致病基因交互作用分子网络构建及功能机制研究

Waardenburg综合征是一种罕见的高遗传异质性疾病，临床特征为感音神经性耳聋及虹膜异色，多与基因突变有关，具体致病机制尚不明确。我们前期发现不同SOX10突变体致等位基因功能细微或极大变化，均能触发其上下游分子网络中基因的动态表达，并首次发现SOX10截短突变后可能触发“旁路途径：SOX10-SOX2-POU4F3”的激活，能补偿增强其转录调控能力。本研究将通过构建不同SOX10突变基因编辑小鼠模型，采用免疫共沉淀联合质谱、单细胞测序等技术，对比分析不同突变情况下SOX10转录水平，以及新发现的分子网络中各基因的功能差异及基因间作用变化，绘制WS致病基因交互作用分子网络；借助统计学及生信手段，推算SOX10基因剂量变化时对分子网络的动态调控模式，探明精密信号调控与遗传异质性对应的理论机制，为后期扩大临床样本量，建立疾病参考模型、探寻发现WS家系的遗传发病机制提供新的研究思路和参考依据。

Waardenburg syndrome (WS), a rare disease with genetic heterogeneity, was characterized by sensorineural hearing loss and heterochromia iris. The pathogenesis of WS has mostly been related to gene mutations but still not fully understood. Our previous studies have found that various SOX10 mutations can cause allele function changing slightly or dominantly, then trigger dynamic expression of the upstream and downstream genes in SOX10-related network. Our group also firstly demonstrated that truncated SOX10 protein might induce the activation of the “SOX10-SOX2-POU3F4” bypass pathway, which could compensate and enhance transcriptional regulation function of SOX10. In this study, we will construct multiple gene-editing mouse models carrying various SOX10 mutations, compare the SOX10 transcription level in different models and observe the functional changes of genes and interaction between genes in SOX10-related network via immune co-precipitation combined mass spectrometry and single-cell sequencing technique, eventually plot the interaction network of WS pathogenic genes. We will also speculate the dynamical regulation model of WS pathogenic gene network with the changes of SOX10 gene dosage via statistical and bioinformatical methods, and explore the theoretical mechanism of precise signal regulation corresponding to genetic heterogeneity. This study can provide new ideas and reference for further WS family genetic pathogenesis studies which aim to include more samples and animal models.