Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51

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

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

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-3β and to altered expression of genes that regulate apoptosis. These results suggest that TJP2- and GSK-3β-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.

Original languageEnglish (US)
Pages (from-to)101-109
Number of pages9
JournalAmerican Journal of Human Genetics
Volume87
Issue number1
DOIs
StatePublished - Jul 9 2010
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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