Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome

Mengnan Li, Shin-ya Nishio, Chie Naruse, Meghan Riddell, Sabrina Sapski, Tatsuya Katsuno, Takao Hikita, Fatemeh Mizapourshafiyi, Fiona M. Smith, Leanne T. Cooper, Min Goo Lee, Masahide Asano, Thomas Boettger, Marcus Krueger, Astrid Wietelmann, Johannes Graumann, Bryan W. Day, Andrew W. Boyd, Stefan Offermanns, Shin-ichiro Kitajiri, Shin-ichi Usami and Masanori Nakayama ()
Additional contact information
Mengnan Li: Max Planck Institute for Heart and Lung Research
Shin-ya Nishio: Shinshu University School of Medicine
Chie Naruse: Kyoto University
Meghan Riddell: Max Planck Institute for Heart and Lung Research
Sabrina Sapski: Max Planck Institute for Heart and Lung Research
Tatsuya Katsuno: Department of Otolaryngology - Head and Neck Surgery Kyoto University Graduate School of Medicine
Takao Hikita: Max Planck Institute for Heart and Lung Research
Fatemeh Mizapourshafiyi: Max Planck Institute for Heart and Lung Research
Fiona M. Smith: QIMR Berghofer Medical Research Institute
Leanne T. Cooper: QIMR Berghofer Medical Research Institute
Min Goo Lee: Yonsei University College of Medicine
Masahide Asano: Kyoto University
Thomas Boettger: Max Planck Institute for Heart and Lung Research
Marcus Krueger: University of Cologne
Astrid Wietelmann: MRI and µCT Service Group, Max Planck Institute for Heart and Lung Research
Johannes Graumann: Scientific Service Group Biomolecular Mass Spectrometry Max Planck Institute for Heart and Lung Research
Bryan W. Day: QIMR Berghofer Medical Research Institute
Andrew W. Boyd: QIMR Berghofer Medical Research Institute
Stefan Offermanns: Max Planck Institute for Heart and Lung Research
Shin-ichiro Kitajiri: Shinshu University School of Medicine
Shin-ichi Usami: Shinshu University School of Medicine
Masanori Nakayama: Max Planck Institute for Heart and Lung Research

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15198-9

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