Lihua Luo
Weiwei Guo
Wei Ren
Chuanhong Liu
Hong Wei
Shiming Yang
Yong Wang
aDepartment of Laboratory Animal Science, College of Basic Medical Science, Army Medical University, Chongqing 400038, China
bCollege of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Beijing 100853, China
cNational Clinical Research Center for Otolaryngologic Diseases, Beijing 100853, China
More InformationCorresponding 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.Keywords: HMG domain,
Inner ear malformation,
Waardenburg syndrome,
Pigment disturbance
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