A truncating CLDN9 variant is associated with autosomal recessive nonsyndromic hearing loss

Hum Genet. 2019 Oct;138(10):1071-1075. doi: 10.1007/s00439-019-02037-1. Epub 2019 Jun 7.


While the importance of tight junctions in hearing is well established, the role of Claudin- 9 (CLDN9), a tight junction protein, in human hearing and deafness has not been explored. Through whole-genome sequencing, we identified a one base pair deletion (c.86delT) in CLDN9 in a consanguineous family from Turkey with autosomal recessive nonsyndromic hearing loss. Three affected members of the family had sensorineural hearing loss (SNHL) ranging from moderate to profound in severity. The variant is predicted to cause a frameshift and produce a truncated protein (p.Leu29ArgfsTer4) in this single-exon gene. It is absent in public databases as well as in over 1000 Turkish individuals, and co-segregates with SNHL in the family. Our in vitro studies demonstrate that the mutant protein does not localize to cell membrane as demonstrated for the wild-type protein. Mice-lacking Cldn9 have been shown to develop SNHL. We conclude that CLDN9 is essential for proper audition in humans and its disruption leads to SNHL in humans.

MeSH terms

  • Claudins / chemistry
  • Claudins / genetics*
  • Claudins / metabolism
  • Computational Biology / methods
  • DNA Mutational Analysis
  • Deafness / diagnosis*
  • Deafness / genetics*
  • Female
  • Frameshift Mutation
  • Genes, Recessive*
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Humans
  • Mutation
  • Pedigree
  • Polymorphism, Genetic
  • Protein Transport
  • Turkey
  • Whole Genome Sequencing


  • CLDN9 protein, human
  • Claudins

Supplementary concepts

  • Nonsyndromic Deafness