Involvement of cochlin binding to sulfated heparan sulfate/heparin in the pathophysiology of autosomal dominant late-onset hearing loss (DFNA9)

PLoS One. 2022 Jul 28;17(7):e0268485. doi: 10.1371/journal.pone.0268485. eCollection 2022.

Abstract

Late-onset non-syndromic autosomal dominant hearing loss 9 (DFNA9) is a hearing impairment caused by mutations in the coagulation factor C homology gene (COCH). COCH encodes for cochlin, a major component of the cochlear extracellular matrix. Though biochemical and genetic studies have characterized the properties of wild-type and mutated cochlins derived from DFNA9, little is known about the underlying pathogenic mechanism. In this study, we established a cochlin reporter cell, which allowed us to monitor the interaction of cochlin with its ligand(s) by means of a β-galactosidase assay. We found a class of highly sulfated glycosaminoglycans (GAGs), heparin, that were selectively bound to cochlin. The interaction was distinctly abrogated by N-desulfation, but not by 2-O- or 6-O-desulfation. The binding of cochlin to GAG was diminished by all of the point mutations found in DFNA9 patients. Through GAG composition analysis and immunostaining using mouse cochlin/immunoglobulin-Fc fusion protein, we identified moderately sulfated GAGs in mouse cochlea tissue; this implies that cochlin binds to such sulfated GAGs in the cochlea. Since GAGs play an important role in cell growth and survival as co-receptors of signal transduction mechanisms, the interaction of cochlin with GAGs in the extracellular matrix could aid the pathological research of autosomal dominant late-onset hearing loss in DFNA9.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Deafness* / genetics
  • Extracellular Matrix Proteins / metabolism
  • Hearing Loss* / genetics
  • Hearing Loss, Sensorineural* / genetics
  • Heparin
  • Heparitin Sulfate
  • Mice
  • Sulfates

Substances

  • Extracellular Matrix Proteins
  • Heparin
  • Heparitin Sulfate
  • Sulfates

Supplementary concepts

  • Deafness, Autosomal Dominant 9

Grants and funding

This work was financially supported by Japan Society for the Promotion of Science (JSPS) KAKENHI grant JP15K14948 (to K.Y.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.