Abstract
Recessive variants of the SLC26A4 gene are an important cause of hereditary hearing impairment. Several transgenic mice with different Slc26a4 variants have been generated. However, none have recapitulated the auditory phenotypes in humans. Of the SLC26A4 variants identified thus far, the p.T721M variant is of interest, as it appears to confer a more severe pathogenicity than most of the other missense variants, but milder pathogenicity than non-sense and frameshift variants. Using a genotype-driven approach, we established a knock-in mouse model homozygous for p.T721M. To verify the pathogenicity of p.T721M, we generated mice with compound heterozygous variants by intercrossing Slc26a4+/T721M mice with Slc26a4919-2A>G/919-2A>G mice, which segregated the c.919-2A > G variant with abolished Slc26a4 function. We then performed serial audiological assessments, vestibular evaluations, and inner ear morphological studies. Surprisingly, both Slc26a4T721M/T721M and Slc26a4919-2A>G/T721M showed normal audiovestibular functions and inner ear morphology, indicating that p.T721M is non-pathogenic in mice and a single p.T721M allele is sufficient to maintain normal inner ear physiology. The evidence together with previous reports on mouse models with Slc26a4 p.C565Y and p.H723R variants, support our speculation that the absence of audiovestibular phenotypes in these mouse models could be attributed to different protein structures at the C-terminus of human and mouse pendrin.
Highlights
Recessive variants in the SLC26A4 (PDS, GeneID: 5172) gene are a common cause of hereditary hearing impairment (HHI)[1]
The scala media was dilated in Slc26a4919-2A>G/919-2A>G mice, but not in Slc26a4T721M/T721M and Slc26a4919-2A>G/T721M mice (RM, Reissner’s membrane; SV, stria vascularis; bar = 150 μm). (C) In the view of the organ of Corti panel, degeneration of hair cells was observed in Slc26a4919-2A>G/919-2A>G mice, but not in the other three groups of mice (IHC, inner hair cells; OHC 1–3, three rows of outer hair cells; bar = 150 μm). (D) Histology of the cochlear hair cells harvested from 3-month-old mice
Pendrin was normally distributed in the spiral prominence (SP) and root cells (RC) in Slc26a4CT721M/T721M and Slc26a4919-2A>G/T721M mice, similar to that in wild-type mice
Summary
Recessive variants in the SLC26A4 (PDS, GeneID: 5172) gene are a common cause of hereditary hearing impairment (HHI)[1]. The auditory phenotypes of Slc26a4L236P/L236P and hH723R Tg mice were milder than those of Slc26a4-/-, Slc26a4loop/loop, and Slc26a4919-2A>G9/919-2A>G mice[11,14], yet the absence of progressive hearing loss could not reflect the clinical symptoms in patients with SLC26A4 mutations. The expression of pendrin in cell lines with p.T721M could not be rescued after salicylate treatment, but that in cell lines with p.H723R could, indicating that p.T721M might confer a stronger pathogenicity than p.H723R15 Based on these results, we hypothesized that mice with the Slc26a4 p.T721M variant might exhibit auditory phenotypes milder than those of c.9192A > G mice but more severe than those of p.H723R mice. We characterized the audiovestibular phenotypes and inner ear pathology in these mouse models (Fig. 1)
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