Identification and functional analysis of a novel missense mutation of PAX3 associated with Waardenburg syndrome type I
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OTOLOGY
Identification and functional analysis of a novel missense mutation of PAX3 associated with Waardenburg syndrome type I Zhijie Niu1,2,4 · Lingyun Mei1,2 · Fen Tang5 · Jiada Li3 · Xueping Wang1,2 · Jie Sun1,2 · Chufeng He1,2 · Hongsheng Cheng1,2 · Yalan Liu1,2 · Xinzhang Cai1,2 · Jian Song1,2 · Yong Feng1,2,3 · Lu Jiang1,2 Received: 6 July 2020 / Accepted: 8 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose 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. Methods 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 cosegregating analysis. The expression, subcellular distribution, and transcriptional activity of the mutant PAX3 protein were analysis to reveal the functional consequences of the mutation. Results 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. Conclusions Our study reports a novel missense PAX3 mutation in a Chinese family and shows haploinsufficiency may be the underlying mechanism for the WS1 phenotype. Keywords Hearing loss · Waardenburg syndrome · Mutation · PAX3 · Haploinsufficiency
Introduction
* Lu Jiang [email protected] 1
Department of Otolaryngology‑Head and Neck Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan, People’s Republic of China
2
Key Laboratory of Otolaryngology Major Disease Research of Hunan Province, Changsha 410008, China
3
Key Laboratory of Medical Genetics of Hunan Province, Central South University, Changsha 410008, China
4
Department of Otolaryngology‑Head and Neck Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530000, China
5
Department of Ophthalmology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530000, China
Waardenburg syndrome (WS) is a rare multigenic auditorypigmentary disorder characterized by moderate to profound sensorineural deafness, dystopia canthorum and hair, eye and skin pigmentation abnormalities, which result from defects in neuralcrestcell (NCC)-derived melanocytes [8]. This disease occurs with a frequency of 1 in 42,000 and is responsible for approximately 1% ~ 3% of congenital heari
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