Toward the Pathogenicity of the SLC26A4 p.C565Y Variant Using a Genetically Driven Mouse Model

Area of Science:

• Genetics
• Otolaryngology
• Molecular Biology

Background:

• Recessive variants in the SLC26A4 gene are a frequent global cause of hearing impairment.
• Previous studies using cell lines and transgenic mice to assess SLC26A4 variant pathogenicity have shown discrepancies with human findings.
• The p.C565Y variant, considered pathogenic in humans, lacked functional consequences in cell line models.

Purpose of the Study:

• To investigate the pathogenicity of the SLC26A4 p.C565Y variant using a genotype-based approach in mice.
• To determine if the p.C565Y variant impacts auditory and vestibular function, inner ear morphology, or pendrin expression in vivo.
• To evaluate the utility of mouse models for understanding SLC26A4-related hearing loss.

Main Methods:

• Generation of knock-in mice heterozygous, homozygous, and compound heterozygous for the Slc26a4 p.C565Y variant.
• Phenotypic characterization including auditory and vestibular function tests.
• Assessment of inner ear morphology and pendrin expression in the generated mouse models.

Main Results:

• Mice with heterozygous, homozygous, and compound heterozygous genotypes for the p.C565Y variant exhibited normal auditory and vestibular functions.
• Inner ear morphology and pendrin expression were normal across all investigated genotypes.
• The p.C565Y variant was determined to be nonpathogenic in mice, with a single allele sufficient for normal inner ear physiology.

Conclusions:

• The SLC26A4 p.C565Y variant does not appear to cause hearing or vestibular dysfunction in mice.
• Significant differences in pathogenicity exist for certain SLC26A4 variants between humans and mouse models.
• Caution is advised when extrapolating findings from animal studies to human SLC26A4-related deafness.