March 16 2020
Li M, Nishio S, Naruse C, Riddell M, Sapski S, Katsuno T, Hikita T, Mizapourshafiy F, Smith FM, Cooper LT, Lee MG, Asano M, Boettger T, Krueger M, Wietelmann A, Graumann J, Day BW, Boyd AW, Offermanns S, Kitajiri S, Usami S, Nakayama M*
2020 Mar 12;11(1):1343. doi: 10.1038/s41467-020-15198-9.
Enlarged vestibular aqueducts (EVA) is one of the most commonly identified inner ear malformations in hearing loss patients including Pendred syndrome. While biallelic mutations of the SLC26A4 gene, encoding pendrin, causes non-syndromic hearing loss with EVA or Pendred syndrome, a considerable number of patients appear to carry mono-allelic mutation. This suggests faulty pendrin regulatory machinery results in hearing loss. Here we identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4. EphA2 forms a protein complex with pendrin controlling pendrin localization, which is disrupted in some pathogenic forms of pendrin. Moreover, point mutations leading to amino acid substitution in the EPHA2 gene are identified from patients bearing mono-allelic mutation of SLC26A4. Ephrin-B2 binds to EphA2 triggering internalization with pendrin inducing EphA2 autophosphorylation weakly. The identified EphA2 mutants attenuate ephrin-B2- but not ephrin-A1-induced EphA2 internalization with pendrin. Our results uncover an unexpected role of the Eph/ephrin system in epithelial function.
At cell-to-cell contact sites, ephrin-B2 may induce pendrin internalization via EphA2 to remove the protein complex. Mono-allelic mutation on the SLC26A4 gene does not cause the symptom, indicating the single allele of the SLC26A4 gene is sufficient for pendrin function. The pendred syndrome patients carrying the mono-allelic mutation on the SCL26A4 genes with the mono-allelic EPHA2 mutation may cause mislocalization of pendrin at the cell-to-cell contact sites, resulting in reduced functional pendrin on the apical surface of the epithelial cells.