Journal article
Variants of human CLDN9 cause mild to profound hearing loss
Human mutation, Vol.42(10), pp.1321-1335
10/2021
DOI: 10.1002/humu.24260
PMCID: PMC8435009
PMID: 34265170
Abstract
Hereditary deafness is clinically and genetically heterogeneous. We investigated deafness segregating as a recessive trait in two families. Audiological examinations revealed an asymmetric mild to profound hearing loss with childhood or adolescent onset. Exome sequencing of probands identified a homozygous c.475G>A;p.(Glu159Lys) variant of CLDN9 (NM_020982.4) in one family and a homozygous c.370_372dupATC;p.(Ile124dup) CLDN9 variant in an affected individual of a second family. Claudin 9 (CLDN9) is an integral membrane protein and constituent of epithelial bicellular tight junctions (TJs) that form semipermeable, paracellular barriers between inner ear perilymphatic and endolymphatic compartments. Computational structural modeling predicts that substitution of a lysine for glutamic acid p.(Glu159Lys) alters one of two cis-interactions between CLDN9 protomers. The p.(Ile124dup) variant is predicted to locally misfold CLDN9 and mCherry tagged p.(Ile124dup) CLDN9 is not targeted to the HeLa cell membrane. In situ hybridization shows that mouse Cldn9 expression increases from embryonic to postnatal development and persists in adult inner ears coinciding with prominent CLDN9 immunoreactivity in TJs of epithelia outlining the scala media. Together with the Cldn9 deaf mouse and a homozygous frameshift of CLDN9 previously associated with deafness, the two bi-allelic variants of CLDN9 described here point to CLDN9 as a bona fide human deafness gene.
Details
- Title: Subtitle
- Variants of human CLDN9 cause mild to profound hearing loss
- Creators
- Memoona Ramzan - University of the PunjabChristophe Philippe - Université de BourgogneInna A Belyantseva - National Institute on Deafness and Other Communication DisordersYoko Nakano - University of IowaCristina Fenollar-Ferrer - National Institute on Deafness and Other Communication DisordersRisa Tona - National Institute on Deafness and Other Communication DisordersRizwan Yousaf - National Institute on Deafness and Other Communication DisordersRasheeda Basheer - University of the PunjabAyesha Imtiaz - National Institute on Deafness and Other Communication DisordersRabia Faridi - National Institute on Deafness and Other Communication DisordersZunaira Munir - University of the PunjabHafiza Idrees - University of the PunjabMidhat Salman - University of the PunjabSophie Nambot - Université de BourgogneAntonio Vitobello - Université de BourgogneSouad Kartti - Mohammed V UniversityOumaima Zarrik - Mohammed V UniversityP Dane Witmer - Johns Hopkins UniversityNara Sobreria - Johns Hopkins UniversityAzeddine Ibrahimi - Mohammed V UniversityBotond Banfi - University of IowaSebastien Moutton - Université de BourgogneThomas B Friedman - National Institute on Deafness and Other Communication DisordersSadaf Naz - University of the Punjab
- Resource Type
- Journal article
- Publication Details
- Human mutation, Vol.42(10), pp.1321-1335
- DOI
- 10.1002/humu.24260
- PMID
- 34265170
- PMCID
- PMC8435009
- NLM abbreviation
- Hum Mutat
- ISSN
- 1059-7794
- eISSN
- 1098-1004
- Grant note
- Z01 DC000039 / Intramural NIH HHS R01 DC014953 / NIDCD NIH HHS Z01 DC000048 / Intramural NIH HHS
- Language
- English
- Date published
- 10/2021
- Academic Unit
- Anatomy and Cell Biology; Otolaryngology; Internal Medicine
- Record Identifier
- 9984284332202771
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