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Functional Studies of Deafness-Associated Pendrin and Prestin Variants
Satoe Takahashi1, Takashi Kojima1,2, Koichiro Wasano1,3
1Department of Otolaryngology-Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
International Journal of Molecular Sciences
|March 13, 2024
Summary
Functional assays reveal that many deafness-associated pendrin and prestin variants impair protein function, impacting hearing. Experimental validation remains crucial for understanding variant pathogenicity, even with computational tools.
Area of Science:
- Molecular Biology
- Genetics
- Audiology
Background:
- Pendrin and prestin are vital membrane proteins for hearing; their dysfunction causes hearing loss.
- Numerous deafness-associated variants of pendrin and prestin exist, but their pathogenic effects are often unclear.
Purpose of the Study:
- To experimentally characterize the functional impact of pendrin and prestin variants associated with hearing loss.
- To evaluate the accuracy of computational tools in predicting variant pathogenicity.
Main Methods:
- In vitro functional assays, including fluorometric anion transport assays for pendrin.
- Nonlinear capacitance (NLC) measurements to assess prestin motor function.
- Comparison of experimental results with AlphaMissense (AM) computational predictions.
Main Results:
- Many pendrin variants on transmembrane domains 9 and 10 showed impaired anion transport activity.
- Functional impairment was quantified for three deafness-associated prestin variants.
- AlphaMissense (AM) scores showed good correlation with experimental data, but some variants were misclassified.
Conclusions:
- Experimental functional assays are essential for accurately determining the pathogenicity of hearing loss-associated pendrin and prestin variants.
- While computational tools like AlphaMissense are valuable, they cannot replace experimental validation.
- This study provides critical data for understanding the molecular basis of hearing loss due to pendrin and prestin dysfunction.
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