The pathogenic roles of the p.R130S prestin variant in DFNB61 hearing loss

Satoe Takahashi, Yingjie Zhou, Mary Ann Cheatham, Kazuaki Homma*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Abstract: DFNB61 is a recessively inherited nonsyndromic hearing loss caused by mutations in SLC26A5, the gene that encodes the voltage-driven motor protein, prestin. Prestin is abundantly expressed in the auditory outer hair cells that mediate cochlear amplification. Two DFNB61-associated SLC26A5 variants, p.W70X and p.R130S, were identified in patients who are compound heterozygous for these nonsense and missense changes (SLC26A5W70X/R130S). Our recent study showed that mice homozygous for p.R130S (Slc26a5R130S/R130S) suffer from hearing loss that is ascribed to significantly reduced motor kinetics of prestin. Given that W70X-prestin is nonfunctional, compound heterozygous Slc26a5R130S/− mice were used as a model for human SLC26A5W70X/R130S. By examining the pathophysiological consequences of p.R130S prestin when it is the sole allele for prestin protein production, we determined that this missense change results in progressive outer hair cell loss in addition to its effects on prestin's motor action. Thus, this study defines the pathogenic roles of p.R130S prestin and identifies a limited time window for potential clinical intervention. (Figure presented.). Key points: The voltage-driven motor protein, prestin, is encoded by SLC26A5 and expressed abundantly in cochlear outer hair cells (OHCs). The importance of prestin for normal hearing was demonstrated in mice lacking prestin; however, none of the specific SLC26A5 variants identified to date in human patients has been experimentally demonstrated to be pathogenic. In this study we used both cell lines and a mouse model to define the pathogenic role of compound heterozygous p.W70X (c.209G>A) and p.R130S (c.390A>C) SLC26A5 variants identified in patients with moderate to profound hearing loss. As in patients, mice carrying one copy of p.R130S Slc26a5 showed OHC dysfunction and progressive degeneration, which results in congenital progressive hearing loss. This is the first functional study reporting pathogenic SLC26A5 variants and pointing to the presence of a therapeutic time window for potential clinical interventions targeting the affected OHCs before they are lost.

Original languageEnglish (US)
Pages (from-to)1199-1210
Number of pages12
JournalJournal of physiology
Volume602
Issue number6
DOIs
StatePublished - Mar 15 2024

Funding

This work was supported by an NIH grant DC017482 (to KH) and by the Knowles Hearing Centre. Some of the imaging work was performed at the Northwestern University Centre for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center.

Keywords

  • DFNB61
  • SLC26A5
  • cochlear amplification
  • electromotility
  • prestin

ASJC Scopus subject areas

  • Physiology

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