Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People's Republic of China.
Key Laboratory of Otolaryngology Major Disease Research of Hunan Province, Changsha, 410008, China.
Eur Arch Otorhinolaryngol. 2021 Aug;278(8):2807-2815. doi: 10.1007/s00405-020-06361-5. Epub 2020 Sep 17.
Waardenburg syndrome type 1 (WS1) is a rare genetic disorder characterized by dystopia canthorum, abnormal iris pigmentation, and congenital hearing loss with variable penetrance.WS1 is caused by mutations in paired box gene 3 (PAX3). The current study aimed to investigate the genetic cause of hearing loss in a four-generation Chinese WS1 family.
The phenotype of the study family was characterized using clinical evaluation and pedigree analysis. Target region high-throughput sequencing system was designed to screen the all coding exons and flanking intronic sequences of the six WS-associated genes. Sanger sequencing was used to identify the causative nucleotide changes and perform the co-segregating analysis. The expression, subcellular distribution, and transcriptional activity of the mutant PAX3 protein were analysis to reveal the functional consequences of the mutation.
Based on diagnostic criteria, the proband of this pedigree classified as WS1. We identified a novel missense mutation (c.117 C > A, p. Asn39Lys) in exon 2 of the PAX3 gene. In vitro, the Asn39Lys PAX3 retained nuclear distribution ability. However, it failed to activate the melanocyte inducing transcription factor (MITF) promoter and impaired the function of WT PAX3.
Our study reports a novel missense PAX3 mutation in a Chinese family and shows haploinsufficiency may be the underlying mechanism for the WS1 phenotype.
Waardenburg 综合征 1 型（WS1）是一种罕见的遗传疾病，其特征为内眦移位、虹膜色素异常和先天性听力损失，具有可变的外显率。WS1 是由配对盒基因 3（PAX3）突变引起的。本研究旨在探讨一个四代中国 WS1 家系听力损失的遗传原因。
通过临床评估和家系分析对研究家系的表型进行特征描述。设计靶向区域高通量测序系统，筛选六个 WS 相关基因的所有编码外显子和侧翼内含子序列。使用 Sanger 测序鉴定致病核苷酸变化，并进行共分离分析。分析突变 PAX3 蛋白的表达、亚细胞分布和转录活性，以揭示突变的功能后果。
根据诊断标准，该家系的先证者被诊断为 WS1。我们在 PAX3 基因的外显子 2 中发现了一个新的错义突变（c.117 C > A，p. Asn39Lys）。在体外，Asn39Lys PAX3 保留了核分布能力。然而，它未能激活黑素细胞诱导转录因子（MITF）启动子，并损害 WT PAX3 的功能。
本研究在一个中国家系中报告了一个新的 PAX3 错义突变，并表明杂合不足可能是 WS1 表型的潜在机制。
