Li, Mengnan, Nishio, Shin-ya ORCID: 0000-0001-6640-2297, Naruse, Chie, Riddell, Meghan, Sapski, Sabrina, Katsuno, Tatsuya, Hikita, Takao, Mizapourshafiyi, Fatemeh, Smith, Fiona M., Cooper, Leanne T., Lee, Min Goo ORCID: 0000-0001-7436-012X, Asano, Masahide, Boettger, Thomas ORCID: 0000-0003-4280-8449, Krueger, Marcus, Wietelmann, Astrid, Graumann, Johannes ORCID: 0000-0002-3015-5850, Day, Bryan W., Boyd, Andrew W., Offermanns, Stefan, Kitajiri, Shin-ichiro, Usami, Shin-ichi and Nakayama, Masanori (2020). Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Li, MengnanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nishio, Shin-yaUNSPECIFIEDorcid.org/0000-0001-6640-2297UNSPECIFIED
Naruse, ChieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riddell, MeghanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sapski, SabrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Katsuno, TatsuyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hikita, TakaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mizapourshafiyi, FatemehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, Fiona M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cooper, Leanne T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Min GooUNSPECIFIEDorcid.org/0000-0001-7436-012XUNSPECIFIED
Asano, MasahideUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boettger, ThomasUNSPECIFIEDorcid.org/0000-0003-4280-8449UNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wietelmann, AstridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graumann, JohannesUNSPECIFIEDorcid.org/0000-0002-3015-5850UNSPECIFIED
Day, Bryan W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boyd, Andrew W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Offermanns, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kitajiri, Shin-ichiroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Usami, Shin-ichiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nakayama, MasanoriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-341084
DOI: 10.1038/s41467-020-15198-9
Journal or Publication Title: Nat. Commun.
Volume: 11
Number: 1
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOTYPE-PHENOTYPE CORRELATION; HEARING-LOSS; SYNDROME GENE; PDS GENE; VESTIBULAR AQUEDUCT; RECEPTORS; EPHRIN-B2; EXPRESSION; MORPHOGENESIS; ENLARGEMENTMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34108

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