PUBLICATION

cdh23 affects congenital hearing loss through regulating purine metabolism

Authors
Yang, S., Xie, B.L., Dong, X.P., Wang, L.X., Zhu, G.H., Wang, T., Wu, W.J., Lai, R.S., Tao, R., Guan, M.X., Chen, F.Y., Tan, D.H., Deng, Z., Xie, H.P., Zeng, Y., Xiao, Z.A., Xie, D.H.
ID
ZDB-PUB-230814-46
Date
2023
Source
Frontiers in molecular neuroscience   16: 10795291079529 (Journal)
Registered Authors
Keywords
ATP, Cdh23, congenital hearing loss, gene knockout, metabolism, regulatory network
MeSH Terms
none
PubMed
37575969 Full text @ Front. Mol. Neurosci.
Abstract
The 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.
In 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.
The 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.
In 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.
Genes / Markers
Figures
Figure Gallery (8 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zf4078
    Small Deletion
    zf4079
      Small Deletion
      1 - 2 of 2
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      Human Disease / Model
      Human Disease Fish Conditions Evidence
      nonsyndromic deafnessTAS
      1 - 1 of 1
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      Sequence Targeting Reagents
      Target Reagent Reagent Type
      cdh23CRISPR4-cdh23CRISPR
      cdh23CRISPR5-cdh23CRISPR
      1 - 2 of 2
      Show
      Fish
      Antibodies
      No data available
      Orthology
      No data available
      Engineered Foreign Genes
      No data available
      Mapping
      No data available