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Hum Genet. 2019 Jun 7. doi: 10.1007/s00439-019-02037-1. [Epub ahead of print]

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

Author information

1
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue BRB-610 (M-860), Miami, FL, USA.
2
Department of Otorhinolaryngology, Dicle University School of Medicine, Diyarbakır, Turkey.
3
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
4
Department of Audiology, Ankara University Health Sciences Faculty, Ankara, Turkey.
5
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue BRB-610 (M-860), Miami, FL, USA. mtekin@med.miami.edu.
6
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA. mtekin@med.miami.edu.
7
Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, USA. mtekin@med.miami.edu.

Abstract

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.

PMID:
31175426
DOI:
10.1007/s00439-019-02037-1

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