cdh23 affects congenital hearing loss through regulating purine metabolism

Frontiers in Molecular Neuroscience

Molecular Neuroscience

Zhong Deng¹  Dong-hui Tan¹  Gang-hua Zhu²  Shu Yang²  Rong Tao²  Zi-an Xiao²  Wei-jing Wu²  Ruo-sha Lai²  Ding-hua Xie²  Tian Wang²  Min-xin Guan³  Bing-Lin Xie⁴  Hua-ping Xie⁴  Fang-yi Chen⁵  Xiao-ping Dong⁶  Yong Zeng⁶  Ling-xiang Wang⁶ 

[1]Department of Otolaryngology—Head and Neck Surgery, The Affiliated Hospital of Xiang Nan College, Chenzhou, China

[2]Department of Otorhinolaryngology—Head & Neck Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

[3]Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China

[4]Department of Human Genetics, Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, Zhejiang, China

[5]Laboratory of Animal Nutrition and Human Health, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, College of Life Science, Hunan Normal University, Changsha, Hunan, China

[6]Shenzhen Key Laboratory of Smart Healthcare Engineering, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, China

[7]The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, Hunan, China

关键词: congenital hearing loss;    Cdh23;    gene knockout;    ATP;    metabolism;    regulatory network;   

DOI  :  10.3389/fnmol.2023.1079529

 received in 2022-10-25, accepted in 2023-02-13,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionThe pathogenic gene CDH23 plays a pivotal role in tip links, which is indispensable for mechanoelectrical transduction in the hair cells. However, the underlying molecular mechanism and signal regulatory networks that influence deafness is still largely unknown.MethodsIn this study, a congenital deafness family, whole exome sequencing revealed a new mutation in the pathogenic gene CDH23, subsequently; the mutation has been validated using Sanger sequencing method. Then CRISPR/Cas9 technology was employed to knockout zebrafish cdh23 gene. Startle response experiment was used to compare with wide-type, the response to sound stimulation between wide-type and cdh23−/−. To further illustrate the molecular mechanisms underlying congenital deafness, comparative transcriptomic profiling and multiple bioinformatics analyses were performed.ResultsThe YO-PRO-1 assay result showed that in cdh23 deficient embryos, the YO-PRO-1 signal in inner ear and lateral line neuromast hair cells were completely lost. Startle response experiment showed that compared with wide-type, the response to sound stimulation decreased significantly in cdh23 mutant larvae. Comparative transcriptomic showed that the candidate genes such as atp1b2b and myof could affect hearing by regulating ATP production and purine metabolism in a synergetic way with cdh23. RT-qPCR results further confirmed the transcriptomics results. Further compensatory experiment showed that ATP treated cdh23−/− embryos can partially recover the mutant phenotype.ConclusionIn conclusion, our study may shed light on deciphering the principal mechanism and provide a potential therapeutic method for congenital hearing loss under the condition of CDH23 mutation.

【 授权许可】

Unknown   
Copyright © 2023 Yang, Xie, Dong, Wang, Zhu, Wang, Wu, Lai, Tao, Guan, Chen, Tan, Deng, Xie, Zeng, Xiao and Xie.