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Genomic Duplication and Overexpression of TJP2/ZO-2 Leads to Altered Expression of Apoptosis Genes

Summary: REPORT
Genomic Duplication and Overexpression of TJP2/ZO-2
Leads to Altered Expression of Apoptosis Genes
in Progressive Nonsyndromic Hearing Loss DFNA51
Tom Walsh,1,8 Sarah B. Pierce,1,8 Danielle R. Lenz,2 Zippora Brownstein,2 Orit Dagan-Rosenfeld,2
Hashem Shahin,3 Wendy Roeb,1 Shane McCarthy,4 Alex S. Nord,1 Carlos R. Gordon,5 Ziva Ben-Neriah,6
Jonathan Sebat,4,9 Moien Kanaan,3 Ming K. Lee,1 Moshe Frydman,2,7 Mary-Claire King,1,*
and Karen B. Avraham2,*
Age-related hearing loss is due to death over time, primarily by apoptosis, of hair cells in the inner ear. Studies of mutant genes respon-
sible 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-3b and to altered expres-
sion of genes that regulate apoptosis. These results suggest that TJP2- and GSK-3b-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.
Age-related hearing loss is an extremely common problem
worldwide. It is caused by the loss over time, primarily


Source: Avraham, Karen - Department of Human Genetics and Molecular Medicine, Tel Aviv University


Collections: Biology and Medicine