Genomic Duplication and Overexpression of TJP2/ZO-2 Leads to Altered Expression of Apoptosis Genes in Progressive Nonsyndromic Hearing Loss DFNA51

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2010 Jul 7

PMID 20602916

Citations 51

Authors

Tom Walsh

Sarah B Pierce

Danielle R Lenz

Zippora Brownstein

Orit Dagan-Rosenfeld

Hashem Shahin

Wendy Roeb

Shane McCarthy

Alex S Nord

Carlos R Gordon

Ziva Ben-Neriah

Jonathan Sebat

Moien Kanaan

Ming K Lee

Moshe Frydman

Mary-Claire King

Karen B Avraham

Affiliations

Soon will be listed here.

Abstract

Age-related hearing loss is due to death over time, primarily by apoptosis, of hair cells in the inner ear. Studies of mutant genes responsible for inherited progressive hearing loss have suggested possible mechanisms for hair cell death, but critical connections between these mutations and the causes of progressive hearing loss have been elusive. In an Israeli kindred, dominant, adult-onset, progressive nonsyndromic hearing loss DFNA51 is due to a tandem inverted genomic duplication of 270 kb that includes the entire wild-type gene encoding the tight junction protein TJP2 (ZO-2). In the mammalian inner ear, TJP2 is expressed mainly in tight junctions, and also in the cytoplasm and nuclei. TJP2 expression normally decreases with age from embryonic development to adulthood. In cells of affected family members, TJP2 transcript and protein are overexpressed, leading to decreased phosphorylation of GSK-3beta and to altered expression of genes that regulate apoptosis. These results suggest that TJP2- and GSK-3beta-mediated increased susceptibility to apoptosis of cells of the inner ear is the mechanism for adult-onset hearing loss in this kindred and may serve as one model for age-related hearing loss in the general population.

Citing Articles

A feedback circuitry involving γ-actin, β-actin and nonmuscle myosin-2 A controls tight junction and apical cortex mechanics.

Mauperin M, Sun Y, Glandorf T, Oswald T, Klatt N, Geil B Nat Commun. 2025; 16(1):2514.

PMID: 40082413 PMC: 11906862. DOI: 10.1038/s41467-025-57428-y.

The known structural variations in hearing loss and their diagnostic approaches: a comprehensive review.

Naghinejad M, Parvizpour S, Shekari Khaniani M, Mehri M, Mansoori Derakhshan S, Amirfiroozy A Mol Biol Rep. 2025; 52(1):131.

PMID: 39821465 DOI: 10.1007/s11033-025-10231-w.

Detection of regions of homozygosity in an unusual case of frontonasal dysplasia.

Paz-Y-Mino C, Vargas-Vera R, Placencia-Ibadango M, Vargas-Silva K, Garcia-Hernandez J, Balarezo-Diaz T Mol Cytogenet. 2024; 17(1):25.

PMID: 39482767 PMC: 11529214. DOI: 10.1186/s13039-024-00693-1.

Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse.

Zhu G, Huang Y, Zhang L, Yan K, Qiu C, He Y EMBO Mol Med. 2023; 15(11):e17611.

PMID: 37691516 PMC: 10630877. DOI: 10.15252/emmm.202317611.

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review.

Alde M, Cantarella G, Zanetti D, Pignataro L, La Mantia I, Maiolino L Biomedicines. 2023; 11(6).

PMID: 37371710 PMC: 10296186. DOI: 10.3390/biomedicines11061616.

References

Veenman L, Papadopoulos V, Gavish M . Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response. Curr Pharm Des. 2007; 13(23):2385-405. DOI: 10.2174/138161207781368710. View

Haake S, Dinh C, Chen S, Eshraghi A, van de Water T . Dexamethasone protects auditory hair cells against TNFalpha-initiated apoptosis via activation of PI3K/Akt and NFkappaB signaling. Hear Res. 2009; 255(1-2):22-32. DOI: 10.1016/j.heares.2009.05.003. View

Park H, Kim H, Bae G, Seo S, Kim D, Jung W . Selective GSK-3beta inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells. Hear Res. 2009; 257(1-2):53-62. DOI: 10.1016/j.heares.2009.08.001. View

Bailey J, Gu Z, Clark R, Reinert K, Samonte R, Schwartz S . Recent segmental duplications in the human genome. Science. 2002; 297(5583):1003-7. DOI: 10.1126/science.1072047. View

Tadros S, DSouza M, Zhu X, Frisina R . Apoptosis-related genes change their expression with age and hearing loss in the mouse cochlea. Apoptosis. 2008; 13(11):1303-21. PMC: 2829878. DOI: 10.1007/s10495-008-0266-x. View

Brenner D, Mak T . Mitochondrial cell death effectors. Curr Opin Cell Biol. 2009; 21(6):871-7. DOI: 10.1016/j.ceb.2009.09.004. View

Linseman D, Butts B, Precht T, Phelps R, Le S, Laessig T . Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci. 2004; 24(44):9993-10002. PMC: 6730230. DOI: 10.1523/JNEUROSCI.2057-04.2004. View

Kwan T, White P, Segil N . Development and regeneration of the inner ear. Ann N Y Acad Sci. 2009; 1170:28-33. PMC: 7245053. DOI: 10.1111/j.1749-6632.2009.04484.x. View

Cheng A, Cunningham L, Rubel E . Mechanisms of hair cell death and protection. Curr Opin Otolaryngol Head Neck Surg. 2005; 13(6):343-8. DOI: 10.1097/01.moo.0000186799.45377.63. View

10.

Carlton V, Harris B, Puffenberger E, Batta A, Knisely A, Robinson D . Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nat Genet. 2003; 34(1):91-6. DOI: 10.1038/ng1147. View

11.

Kurima K, Peters L, Yang Y, Riazuddin S, Ahmed Z, Naz S . Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet. 2002; 30(3):277-84. DOI: 10.1038/ng842. View

12.

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):RESEARCH0034. PMC: 126239. DOI: 10.1186/gb-2002-3-7-research0034. View

13.

Riva C, Donadieu E, Magnan J, Lavieille J . Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea. Exp Gerontol. 2006; 42(4):327-36. DOI: 10.1016/j.exger.2006.10.014. View

14.

Maurer U, Charvet C, Wagman A, Dejardin E, Green D . Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006; 21(6):749-60. DOI: 10.1016/j.molcel.2006.02.009. View

15.

Chipuk J, Moldoveanu T, Llambi F, Parsons M, Green D . The BCL-2 family reunion. Mol Cell. 2010; 37(3):299-310. PMC: 3222298. DOI: 10.1016/j.molcel.2010.01.025. View

16.

Riazuddin S, Ahmed Z, Fanning A, Lagziel A, Kitajiri S, Ramzan K . Tricellulin is a tight-junction protein necessary for hearing. Am J Hum Genet. 2006; 79(6):1040-51. PMC: 1698716. DOI: 10.1086/510022. View

17.

Walsh T, McClellan J, McCarthy S, Addington A, Pierce S, Cooper G . Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008; 320(5875):539-43. DOI: 10.1126/science.1155174. View

18.

Matter K, Balda M . Epithelial tight junctions, gene expression and nucleo-junctional interplay. J Cell Sci. 2007; 120(Pt 9):1505-11. DOI: 10.1242/jcs.005975. View

19.

Hu B, Cai Q, Manohar S, Jiang H, Ding D, Coling D . Differential expression of apoptosis-related genes in the cochlea of noise-exposed rats. Neuroscience. 2009; 161(3):915-25. PMC: 2692744. DOI: 10.1016/j.neuroscience.2009.03.072. View

20.

Hilgert N, Alasti F, Dieltjens N, Pawlik B, Wollnik B, Uyguner O . Mutation analysis of TMC1 identifies four new mutations and suggests an additional deafness gene at loci DFNA36 and DFNB7/11. Clin Genet. 2008; 74(3):223-32. PMC: 4732719. DOI: 10.1111/j.1399-0004.2008.01053.x. View