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The R130S mutation significantly affects the function of prestin, the outer hair cell motor protein

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Abstract

A missense mutation, R130S, was recently found in the prestin gene, SLC26A5, of patients with moderate to severe hearing loss (DFNB61). In order to define the pathology of hearing loss associated with this missense mutation, a recombinant prestin construct harboring the R130S mutation (R130S-prestin) was generated, and its functional consequences examined in a heterologous expression system. We found that R130S-prestin targets the plasma membrane but less efficiently compared to wild-type. The voltage operating point and voltage sensitivity of the motor function of R130S-prestin were similar to wild-type prestin. However, the motor activity of R130S-prestin is greatly reduced at higher voltage stimulus frequencies, indicating a reduction in motor kinetics. Our study thus provides experimental evidence that supports a causal relationship between the R130S mutation in the prestin gene and hearing loss found in patients with this missense mutation.

Key message

  • Membrane targeting of prestin is impaired by the R130S missense mutation.

  • The fast motor kinetics of prestin is impaired by the R130S missense mutation.

  • Our study strongly suggests that the prestin R130S missense mutation is pathogenic.

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Abbreviations

OHC:

Outer hair cell

NLC:

Nonlinear capacitance

wt:

Wild type

KO:

Knockout

ECFP:

Enhanced cyan fluorescent protein

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Acknowledgments

Nicole Chen (Stevenson High School, Lincolnshire, IL) contributed to the generation of the R130S prestin construct and the data collection at the early stage of this study. Imaging was performed at the Northwestern University Center for Advanced Microscopy, supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. This work was supported by the National Institutes of Health grants [DC014553 to K.H., DC00089 to M.A.C., and DC011813 to J.Z.], and the Hugh Knowles Hearing Center.

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Authors and Affiliations

  1. Department of Otolaryngology – Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, 303 E Chicago Ave, Chicago, IL, 60611, USA

    Satoe Takahashi, Jing Zheng & Kazuaki Homma

  2. The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University, Evanston, IL, 60208, USA

    Mary Ann Cheatham, Jing Zheng & Kazuaki Homma

  3. Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, 60208, USA

    Mary Ann Cheatham

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  1. Satoe Takahashi
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Correspondence to Kazuaki Homma.

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Takahashi, S., Cheatham, M.A., Zheng, J. et al. The R130S mutation significantly affects the function of prestin, the outer hair cell motor protein. J Mol Med 94, 1053–1062 (2016). https://doi.org/10.1007/s00109-016-1410-7

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  • DOI: https://doi.org/10.1007/s00109-016-1410-7

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