Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome

西尾, 信哉, 成瀬, 智恵, 勝野, 達也, 匹田, 貴夫, 浅野, 雅秀, 北尻, 真一郎, 宇佐美, 真一, 中山, 雅敬, Smith, Fiona M., Cooper, Leanne T., Lee, Min Goo, Asano, Masahide, Boettger, Thomas, Krueger, Marcus, Wietelmann, Astrid, Graumann, Johannes, Day, Bryan W., Boyd, Andrew W., Offermanns, Stefan, Kitajiri, Shin-ichiro, Usami, Shin-ichi, Nakayama, Masanori

Enlarged vestibular aqueduct (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.

Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome

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Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome

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