Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro

Marie Wattenhofer, Alexandre Reymond, Véronique Falciola, Anne Charollais, Dorothée Caille, Christelle Borel, Robert Lyle, Xavier P. Estivill, Michael B. Petersen, Paolo Meda, Stylianos E. Antonarakis

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Mutations in claudin 14 (CLDN14) cause nonsyndromic DFNB29 deafness in humans. The analysis of a murine model indicated that this phenotype is associated with degeneration of hair cells, possibly due to cation overload. However, the mechanism linking these alterations to CLDN14 mutations is unknown. To investigate this mechanism, we compared the ability of wild-type and missense mutant CLDN14 to form tight junctions. Ectopic expression in L mouse fibroblasts (LM cells) of wild-type CLDN14 protein induced the formation of tight junctions, while both the c.254T>A (p.V85D) mutant, previously identified in a Pakistani family, and the c.301 G>A (p.G101R) mutant, identified in this study through the screen of 183 Spanish and Greek patients affected with sporadic nonsyndromic deafness, failed to form such junctions. However, the two mutant proteins differed in their ability to localize at the plasma membrane. We further identified hitherto undescribed exons of CLDN14 that are utilized in alternative spliced transcripts. We demonstrated that different mutations of CLDN14 impaired by different mechanisms the ability of the protein to form tight junctions. Our results indicate that the ability of CLDN14 to be recruited to these junctions is crucial for the hearing process.

Original languageEnglish
Pages (from-to)543-549
Number of pages7
JournalHuman Mutation
Volume25
Issue number6
DOIs
Publication statusPublished - Jun 2005
Externally publishedYes

Fingerprint

Claudins
Tight Junctions
Mutant Proteins
Aptitude
Mutation
claudin 14
In Vitro Techniques
Hearing
Cations
Exons
Fibroblasts
Cell Membrane
Phenotype

Keywords

  • CLDN14
  • Deafness
  • DFNB29
  • Tight junctions

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Wattenhofer, M., Reymond, A., Falciola, V., Charollais, A., Caille, D., Borel, C., ... Antonarakis, S. E. (2005). Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro. Human Mutation, 25(6), 543-549. https://doi.org/10.1002/humu.20172

Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro. / Wattenhofer, Marie; Reymond, Alexandre; Falciola, Véronique; Charollais, Anne; Caille, Dorothée; Borel, Christelle; Lyle, Robert; Estivill, Xavier P.; Petersen, Michael B.; Meda, Paolo; Antonarakis, Stylianos E.

In: Human Mutation, Vol. 25, No. 6, 06.2005, p. 543-549.

Research output: Contribution to journalArticle

Wattenhofer, M, Reymond, A, Falciola, V, Charollais, A, Caille, D, Borel, C, Lyle, R, Estivill, XP, Petersen, MB, Meda, P & Antonarakis, SE 2005, 'Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro', Human Mutation, vol. 25, no. 6, pp. 543-549. https://doi.org/10.1002/humu.20172
Wattenhofer M, Reymond A, Falciola V, Charollais A, Caille D, Borel C et al. Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro. Human Mutation. 2005 Jun;25(6):543-549. https://doi.org/10.1002/humu.20172
Wattenhofer, Marie ; Reymond, Alexandre ; Falciola, Véronique ; Charollais, Anne ; Caille, Dorothée ; Borel, Christelle ; Lyle, Robert ; Estivill, Xavier P. ; Petersen, Michael B. ; Meda, Paolo ; Antonarakis, Stylianos E. / Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro. In: Human Mutation. 2005 ; Vol. 25, No. 6. pp. 543-549.
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