SLC26A5 – autosomal recessive nonsyndromic hearing loss 61

SLC26A5-associated DFNB61 is an autosomal recessive nonsyndromic hearing loss characterized by congenital to progressive sensorineural impairment due to dysfunction of prestin, the outer hair cell motor protein. Prestin is essential for cochlear amplification, and loss of its function reduces electromotility and raises auditory thresholds.

Genetic evidence for DFNB61 arises from compound heterozygous variants in affected individuals. Two unrelated probands were identified with c.210G>A (p.Trp70Ter) and c.390A>C (p.Arg130Ser) SLC26A5 changes, each inherited in trans, leading to moderate-to-profound hearing loss ([PMID:37662362]) and replicated in a separate cohort ([PMID:38431907]). No additional segregation beyond the index cases has been reported.

Functional studies in heterologous systems and knock-in mice have established the pathogenicity of these variants. R130S-prestin exhibits reduced membrane targeting and significantly slowed motor kinetics at high stimulus frequencies ([PMID:27041369]). Mice homozygous for p.Arg130Ser or compound heterozygous for R130S/– show progressive outer hair cell loss and hearing deficits, confirming a loss-of-function mechanism and defining a critical intervention window ([PMID:37662362], [PMID:38431907]).

Additional missense variants p.Ala100Thr and p.Pro119Ser impair prestin surface expression to ~30% of wild-type levels, resulting in frequency-dependent hearing loss in mouse models and demonstrating that partial reduction of prestin is disease-causing ([PMID:38826260]).

A common splice variant, c.-53-2A>G (IVS2-2A>G), occurs at similar frequencies in hearing-impaired and control populations and shows alternative splice acceptor usage in silico, suggesting it is likely benign ([PMID:16086836]).

Integrating genetic and experimental data, SLC26A5 meets a Moderate ClinGen gene–disease validity score: limited patient numbers but consistent in vivo and in vitro evidence of pathogenicity. These findings support clinical genetic testing for DFNB61 and highlight a therapeutic window targeting outer hair cell preservation.

References

• The Journal of Physiology • 2024 • The pathogenic roles of the p.R130S prestin variant in DFNB61 hearing loss PMID:38431907
• Journal of Molecular Medicine • 2016 • The R130S mutation significantly affects the function of prestin, the outer hair cell motor protein. PMID:27041369
• bioRxiv • 2024 • The frequency dependence of prestin-mediated fast electromotility for mammalian cochlear amplification. PMID:38826260
• Human Molecular Genetics • 2005 • High frequency of the IVS2-2A>G DNA sequence variation in SLC26A5, encoding the cochlear motor protein prestin, precludes its involvement in hereditary hearing loss. PMID:16086836
• Nature Communications • 2023 • Functional validation of DFNB61-associated SLC26A5 variants in murine models and cell assays PMID:37662362

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