A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain

Hyun Ju Cho, Hong Joon Park, Maria Trexler, Hanka Venselaar, Kyu Yup Lee, Nahid G. Robertson, Jeong In Baek, Beom Sik Kang, Cynthia C. Morton, Gert Vriend, László Patthy, Un Kyung Kim

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Mutations in COCH have been associated with autosomal dominant nonsyndromic hearing loss (DFNA9) and are frequently accompanied by vestibular hypofunction. Here, we report identification of a novel missense mutation, p.F527C, located in the vWFA2 domain in members of a Korean family with late-onset and progressive hearing loss. To assess the molecular characteristics of this cochlin mutant, we constructed both wild-type and mutant cochlin constructs and transfected these into mammalian cell lines. Results of immunocytochemistry analysis demonstrated localization of the cochlin mutant in the endoplasmic reticulum/Golgi complex, whereas western blot analyses of cell lysates revealed that the mutant cochlin tends to form covalent complexes that are retained in the cell. Biochemical analyses of recombinant vWFA2 domain of cochlin carrying the p.F527C mutation revealed that the mutation increases propensity of the protein to form covalent disulfide-bonded dimers and affects the structural stability but not the collagen-affinity of the vWFA2 domain. We suggest that the instability of mutant cochlin is the major driving force for cochlin aggregation in the inner ear in DFNA9 patients carrying the COCH p.F527C mutation.

Original languageEnglish
Pages (from-to)1321-1331
Number of pages11
JournalJournal of Molecular Medicine
Volume90
Issue number11
DOIs
Publication statusPublished - Nov 2012

Keywords

  • Cochlin
  • DFNA9
  • Mutation
  • Nonsyndromic hearing loss
  • Protein stability

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain'. Together they form a unique fingerprint.

  • Cite this

    Cho, H. J., Park, H. J., Trexler, M., Venselaar, H., Lee, K. Y., Robertson, N. G., Baek, J. I., Kang, B. S., Morton, C. C., Vriend, G., Patthy, L., & Kim, U. K. (2012). A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain. Journal of Molecular Medicine, 90(11), 1321-1331. https://doi.org/10.1007/s00109-012-0911-2