The p.Cys169Tyr variant of connexin 26 is not a polymorphism

Francesco Zonta, Giorgia Girotto, Damiano Buratto, Giulia Crispino, Anna Morgan, Khalid Abdulhadi, Moza K. Al-Kowari, Ramin Badii, Paolo Gasparini, Fabio Mammano

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Mutations in the GJB2 gene, which encodes the gap junction protein connexin 26 (Cx26), are the primary cause of hereditary prelingual hearing impairment. Here, the p.Cys169Tyr missense mutation of Cx26 (Cx26C169Y), previously classified as a polymorphism, has been identified as causative of severe hearing loss in two Qatari families.We have analyzed the effect of this mutation using a combination of confocal immunofluorescence microscopy and molecular dynamics simulations. At the cellular level, our results show that the mutant protein fails to form junctional channels in HeLa transfectants despite being correctly targeted to the plasma membrane. At the molecular level, this effect can be accounted for by disruption of the disulfide bridge that Cys169 forms with Cys64 in the wild-type structure (Cx26WT). The lack of the disulfide bridge in the Cx26C169Y protein causes a spatial rearrangement of two important residues, Asn176 and Thr177. In the Cx26WT protein, these residues play a crucial role in the intra-molecular interactions that permit the formation of an intercellular channel by the head-to-head docking of two opposing hemichannels resident in the plasma membrane of adjacent cells. Our results elucidate the molecular pathogenesis of hereditary hearing loss due to the connexin mutation and facilitate the understanding of its role in both healthy and affected individuals.

Original languageEnglish
Pages (from-to)2641-2648
Number of pages8
JournalHuman Molecular Genetics
Volume24
Issue number9
DOIs
Publication statusPublished - 2015

Fingerprint

Hearing Loss
Connexins
Disulfides
Mutation
Cell Membrane
Missense Mutation
Mutant Proteins
Molecular Dynamics Simulation
Fluorescence Microscopy
Confocal Microscopy
Proteins
Genes
Connexin 26

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Zonta, F., Girotto, G., Buratto, D., Crispino, G., Morgan, A., Abdulhadi, K., ... Mammano, F. (2015). The p.Cys169Tyr variant of connexin 26 is not a polymorphism. Human Molecular Genetics, 24(9), 2641-2648. https://doi.org/10.1093/hmg/ddv026

The p.Cys169Tyr variant of connexin 26 is not a polymorphism. / Zonta, Francesco; Girotto, Giorgia; Buratto, Damiano; Crispino, Giulia; Morgan, Anna; Abdulhadi, Khalid; Al-Kowari, Moza K.; Badii, Ramin; Gasparini, Paolo; Mammano, Fabio.

In: Human Molecular Genetics, Vol. 24, No. 9, 2015, p. 2641-2648.

Research output: Contribution to journalArticle

Zonta, F, Girotto, G, Buratto, D, Crispino, G, Morgan, A, Abdulhadi, K, Al-Kowari, MK, Badii, R, Gasparini, P & Mammano, F 2015, 'The p.Cys169Tyr variant of connexin 26 is not a polymorphism', Human Molecular Genetics, vol. 24, no. 9, pp. 2641-2648. https://doi.org/10.1093/hmg/ddv026
Zonta F, Girotto G, Buratto D, Crispino G, Morgan A, Abdulhadi K et al. The p.Cys169Tyr variant of connexin 26 is not a polymorphism. Human Molecular Genetics. 2015;24(9):2641-2648. https://doi.org/10.1093/hmg/ddv026
Zonta, Francesco ; Girotto, Giorgia ; Buratto, Damiano ; Crispino, Giulia ; Morgan, Anna ; Abdulhadi, Khalid ; Al-Kowari, Moza K. ; Badii, Ramin ; Gasparini, Paolo ; Mammano, Fabio. / The p.Cys169Tyr variant of connexin 26 is not a polymorphism. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 9. pp. 2641-2648.
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