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; Masanori Nakayama

doi:10.1038/s41467-020-15198-9

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 KitajiriShin ichi Usami, Masanori Nakayama

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20 Citations (Scopus)

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.

Original language	English
Article number	1343
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15198-9
Publication status	Published - Dec 1 2020
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-020-15198-9

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Li, M., Nishio, S. Y., Naruse, C., Riddell, M., Sapski, S., Katsuno, T., Hikita, T., Mizapourshafiyi, F., Smith, F. M., Cooper, L. T., Lee, M. G., Asano, M., Boettger, T., Krueger, M., Wietelmann, A., Graumann, J., Day, B. W., Boyd, A. W., Offermanns, S., ... Nakayama, M. (2020). Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome. Nature communications, 11(1), Article 1343. https://doi.org/10.1038/s41467-020-15198-9

Li, M, Nishio, SY, Naruse, C, Riddell, M, Sapski, S, Katsuno, T, Hikita, T, Mizapourshafiyi, F, Smith, FM, Cooper, LT, Lee, MG, Asano, M, Boettger, T, Krueger, M, Wietelmann, A, Graumann, J, Day, BW, Boyd, AW, Offermanns, S, Kitajiri, SI, Usami, SI & Nakayama, M 2020, 'Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome', Nature communications, vol. 11, no. 1, 1343. https://doi.org/10.1038/s41467-020-15198-9

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title = "Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome",

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.",

author = "Mengnan Li and Nishio, {Shin ya} and Chie Naruse and Meghan Riddell and Sabrina Sapski and Tatsuya Katsuno and Takao Hikita and Fatemeh Mizapourshafiyi and Smith, {Fiona M.} and Cooper, {Leanne T.} and Lee, {Min Goo} and Masahide Asano and Thomas Boettger and Marcus Krueger and Astrid Wietelmann and Johannes Graumann and Day, {Bryan W.} and Boyd, {Andrew W.} and Stefan Offermanns and Kitajiri, {Shin ichiro} and Usami, {Shin ichi} and Masanori Nakayama",

note = "Funding Information: Funding for this project was provided by the Excellence Cluster Cardio-Pulmonary System, the German Research Foundation, Deutsche Forschungsgemeinschaft (GRK2213), and Fritz Thyssen Stiftung (Az. 10.14.2.178). M.G.L. was supported by funding from NRF-2013R1A3A2042197 from the National Research Foundation, the Ministry of Science and ICT, Republic of Korea. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41467-020-15198-9",

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T1 - Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome

AU - Li, Mengnan

AU - Nishio, Shin ya

AU - Naruse, Chie

AU - Riddell, Meghan

AU - Sapski, Sabrina

AU - Katsuno, Tatsuya

AU - Hikita, Takao

AU - Mizapourshafiyi, Fatemeh

AU - Smith, Fiona M.

AU - Cooper, Leanne T.

AU - Lee, Min Goo

AU - Asano, Masahide

AU - Boettger, Thomas

AU - Krueger, Marcus

AU - Wietelmann, Astrid

AU - Graumann, Johannes

AU - Day, Bryan W.

AU - Boyd, Andrew W.

AU - Offermanns, Stefan

AU - Kitajiri, Shin ichiro

AU - Usami, Shin ichi

AU - Nakayama, Masanori

N1 - Funding Information: Funding for this project was provided by the Excellence Cluster Cardio-Pulmonary System, the German Research Foundation, Deutsche Forschungsgemeinschaft (GRK2213), and Fritz Thyssen Stiftung (Az. 10.14.2.178). M.G.L. was supported by funding from NRF-2013R1A3A2042197 from the National Research Foundation, the Ministry of Science and ICT, Republic of Korea. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome

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