Phenotypic similarities in pigs with SOX10c.321dupC and SOX10c.325A&amp;gt;T mutations implied the correlation of SOX10 haploinsufficiency with Waardenburg syndrome

Tingting Lin; Lihua Luo; Weiwei Guo; Wei Ren; Chuanhong Liu; Hong Wei; Shiming Yang; Yong Wang

doi:10.1016/j.jgg.2020.12.003

Volume 47 Issue 12

Dec. 2020

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Article Navigation > Journal of Genetics and Genomics > 2020 > 47(12): 770-780

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Phenotypic similarities in pigs with SOX10c.321dupC and SOX10c.325A>T mutations implied the correlation of SOX10 haploinsufficiency with Waardenburg syndrome

doi: 10.1016/j.jgg.2020.12.003

a
Department of Laboratory Animal Science, College of Basic Medical Science, Army Medical University, Chongqing 400038, China
b
College of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Beijing 100853, China
c
National Clinical Research Center for Otolaryngologic Diseases, Beijing 100853, China

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Corresponding author: E-mail address: weihong63528@163.com (Hong Wei); E-mail address: shm_yang@163.com (Shiming Yang); E-mail address: yongw7528@hotmail.com (Yong Wang)
Publish Date: 2020-12-25

Abstract

Abstract

SOX10 is a causative gene of Waardenburg syndrome (WS) that is a rare genetic disorder characterized by hearing loss and pigment disturbance. More than 100 mutations of SOX10 have been found in patients with Type 2 WS (WS2), Type 4 WS (WS4), and more complex syndromes. However, no mutation hotspot has been detected in SOX10, and most cases are sporadic, making it difficult to establish a correlation between the high phenotypic and genetic variability. In this study, a duplication of the 321th cytosine (c.321dupC) was introduced into SOX10 in pigs, which induced premature termination of the translation of SOX10 (p.K108QfsX45). The premature stop codon in Exon 3 triggered the degradation of mutant mRNA through nonsense-mediated mRNA decay. However, SOX10 induced a highly similar phenotype of WS2 with heterogeneous inner ear malformation compared with its adjacent missense mutation SOX10. In addition, a site-saturation mutation analysis of the SOX10 N-terminal nuclear localization signal (n-NLS), where these two mutations located, revealed the correlation between SOX10 haploinsufficiency and WS by an in vitro reporter assay. The analysis combining the in vitro assay with clinical cases may provide a clue to clinical diagnoses.
- HMG domain,
- Inner ear malformation,
- Waardenburg syndrome,
- Pigment disturbance

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References(49)

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