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

Walsh, Tom; Pierce, Sarah B.; Lenz, Danielle R.; Brownstein, Zippora; Dagan‐Rosenfeld, Orit; Shahin, Hashem; Roeb, Wendy; McCarthy, Shane; Nord, Alexander; Gordon, Carlos R.; Ben‐Neriah, Ziva; Sebat, Jonathan; Kanaan, Moien; Lee, Ming K.; Frydman, Moshe; King, Mary Claire; Avraham, Karen B.

doi:10.1016/j.ajhg.2010.05.011

Cited by 92 publications

(83 citation statements)

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“…Overexpression of TJP2 leads to altered expression of apoptosis-related genes, ultimately causing HL. 26 We believe that our study provides a new line of evidence supporting an important role of apoptosis in HL.…”

Section: Discussionmentioning

confidence: 78%

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

et al. 2011

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DFNA5 was first identified as a gene causing autosomal dominant hearing loss (HL). Different mutations have been found, all exerting a highly specific gain-of-function effect, in which skipping of exon 8 causes the HL. Later reports revealed the involvement of the gene in different types of cancer. Epigenetic silencing of DFNA5 in a large percentage of gastric, colorectal and breast tumors and p53-dependent transcriptional activity have been reported, concluding that DFNA5 acts as a tumor suppressor gene in different frequent types of cancer. Despite these data, the molecular function of DFNA5 has not been investigated properly. Previous transfection studies with mutant DFNA5 in yeast and in mammalian cells showed a toxic effect of the mutant protein, which was not seen after transfection of the wild-type protein. Here, we demonstrate that DFNA5 is composed of two domains, separated by a hinge region. The first region induces apoptosis when transfected in HEK293T cells, the second region masks and probably regulates this apoptosis inducing capability. Moreover, the involvement of DFNA5 in apoptosis-related pathways in a physiological setting was demonstrated through gene expression microarray analysis using Dfna5 knockout mice. In view of its important role in carcinogenesis, this finding is expected to lead to new insights on the role of apoptosis in many types of cancer. In addition, it provides a new line of evidence supporting an important role for apoptosis in monogenic and complex forms of HL. Keywords: tumor suppressor; hearing loss; apoptosis; dfna5; cancer; GSEA INTRODUCTION DFNA5 first was discovered in a Dutch family with autosomal dominant hearing loss (HL). 1 Not much was known concerning its cellular function and how its function was related to HL. Recently, a novel mutation in DFNA5 has been identified in a Korean family, totaling five families with DFNA5 HL. 2 These families all have different genomic DFNA5 mutations, but in each case the DFNA5 mRNA transcript skips exon 8, resulting in a frameshift and a premature truncation of the protein. [1][2][3][4][5] These findings have led to the hypothesis that DFNA5-associated HL is attributable to a highly specific gain-of-function mutation, in which skipping of one exon causes disease while mutations in other parts of this gene may not result in HL at all. Further experimental evidence for this hypothesis was provided by the finding that transfection of mutant DFNA5 causes cell death in both yeast 6 and mammalian 7 cells and by the discovery of a new DFNA5 mutation. 8 The latter mutation truncated the protein in the fifth exon, but did not segregate with HL and was present in family members with normal hearing. The hypothesis was further corroborated by a mouse that lacked the Dfna5 protein. This knockout (KO) mouse did not display any HL and, as a consequence, was not a suitable animal model to study DFNA5-associated HL. 9 To date, little information is available on the physiological function of DFNA5. However, since its identification, the small num...

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Section: Discussionmentioning

confidence: 78%

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

et al. 2011

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“…Aside from their role in regulating TJ assembly and stability, TJPs translocate to the nucleus to regulate gene expression (Bauer et al, 2010). Indeed, overexpression of TJP2 and altered expression of apoptosis-related genes may contribute to hearing loss in DFNA51 patients (Walsh et al, 2010). Although we cannot exclude the involvement of intrinsic cellular mechanisms in the pathophysiology of mambo mice, the mitochondrial apoptotic pathway is unlikely to underlie OHC death because no caspase-3 activity was detected in degenerating OHCs.…”

Section: Discussionmentioning

confidence: 99%

“…1). Mutations in the respective genes lead to deafness in mice and humans (Wilcox et al, 2001;Ben-Yosef et al, 2003;Gow et al, 2004;Kitajiri et al, 2004Kitajiri et al, , 2014Nakano et al, 2009;Walsh et al, 2010;Borck et al, 2011;Morozko et al, 2015). To verify whether USP53 acts in a common pathway with any of these proteins, we searched for biochemical interactions.…”

Section: Usp53 Localizes To Tjs In Cochlear Epithelial Cellsmentioning

confidence: 99%

“…In contrast, hearing loss in claudin-9, claudin-14, occludin, tricellulin, and ILDR1-deficient mice has been ascribed to altered leakiness of TJs in the organ of Corti and an increased concentration of K ϩ around the basolateral surfaces of the outer hair cells (OHCs), resulting in hair cell degeneration (Ben-Yosef et al, 2003;Nakano et al, 2009;Nayak et al, 2013;Kitajiri et al, 2014;Morozko et al, 2015). Finally, genomic duplication and overexpression of TJP2 has been linked to nonsyndromic deafness DFNA51 (Walsh et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Progressive Hearing Loss in Mice Carrying a Mutation inUsp53

et al. 2015

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Disordered protein ubiquitination has been linked to neurodegenerative disease, yet its role in inner ear homeostasis and hearing loss is essentially unknown. Here we show that progressive hearing loss in the ethylnitrosourea-generated mambo mouse line is caused by a mutation in Usp53, a member of the deubiquitinating enzyme family. USP53 contains a catalytically inactive ubiquitin-specific protease domain and is expressed in cochlear hair cells and a subset of supporting cells. Although hair cell differentiation is unaffected in mambo mice, outer hair cells degenerate rapidly after the first postnatal week. USP53 colocalizes and interacts with the tight junction scaffolding proteins TJP1 and TJP2 in polarized epithelial cells, suggesting that USP53 is part of the tight junction complex. The barrier properties of tight junctions of the stria vascularis appeared intact in a biotin tracer assay, but the endocochlear potential is reduced in adult mambo mice. Hair cell degeneration in mambo mice precedes endocochlear potential decline and is rescued in cochlear organotypic cultures in low potassium milieu, indicating that hair cell loss is triggered by extracellular factors. Remarkably, heterozygous mambo mice show increased susceptibility to noise injury at high frequencies. We conclude that USP53 is a novel tight junction-associated protein that is essential for the survival of auditory hair cells and normal hearing in mice, possibly by modulating the barrier properties and mechanical stability of tight junctions.

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“…These genes include GJB6, PCDH15, USH1C, MYO3A, SLC26A4, LOXHD1, CDH23, MYO15A, WFS1, TECTA, POU4F3 and the inverted duplication of TJP2. 3,[23][24][25] All known deafness-causing mutations in the Palestinian population were excluded, including mutations in CDH23, MYO7A, MYO15A, OTOF, PJVK, SLC26A4, TECTA, TMHS, TMPRSS3, OTOA, PTPRQ and GPSM2. 22,26,27 Massive parallel sequencing Capture libraries were created and MPS was performed, followed by bioinformatics analysis, as previously described.…”

Section: Gene Exclusionmentioning

confidence: 99%

Novel myosin mutations for hereditary hearing loss revealed by targeted genomic capture and massively parallel sequencing

et al. 2013

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Hereditary hearing loss is genetically heterogeneous, with a large number of genes and mutations contributing to this sensory, often monogenic, disease. This number, as well as large size, precludes comprehensive genetic diagnosis of all known deafness genes. A combination of targeted genomic capture and massively parallel sequencing (MPS), also referred to as next-generation sequencing, was applied to determine the deafness-causing genes in hearing-impaired individuals from Israeli Jewish and Palestinian Arab families. Among the mutations detected, we identified nine novel mutations in the genes encoding myosin VI, myosin VIIA and myosin XVA, doubling the number of myosin mutations in the Middle East. Myosin VI mutations were identified in this population for the first time. Modeling of the mutations provided predicted mechanisms for the damage they inflict in the molecular motors, leading to impaired function and thus deafness. The myosin mutations span all regions of these molecular motors, leading to a wide range of hearing phenotypes, reinforcing the key role of this family of proteins in auditory function. This study demonstrates that multiple mutations responsible for hearing loss can be identified in a relatively straightforward manner by targeted-gene MPS technology and concludes that this is the optimal genetic diagnostic approach for identification of mutations responsible for hearing loss.

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

Cited by 92 publications

References 40 publications

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

Progressive Hearing Loss in Mice Carrying a Mutation inUsp53

Novel myosin mutations for hereditary hearing loss revealed by targeted genomic capture and massively parallel sequencing

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