title: Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51.
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.
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Pierce
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Lenz
authors.forename: Zippora
authors.initials: Z
authors.lastname: Brownstein
authors.forename: Orit
authors.initials: O
authors.lastname: Dagan-Rosenfeld
authors.forename: Hashem
authors.initials: H
authors.lastname: Shahin
authors.forename: Wendy
authors.initials: W
authors.lastname: Roeb
authors.forename: Shane
authors.initials: S
authors.lastname: McCarthy
authors.forename: Alex S
authors.initials: AS
authors.lastname: Nord
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Gordon
authors.forename: Ziva
authors.initials: Z
authors.lastname: Ben-Neriah
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sebat
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Moshe
authors.initials: M
authors.lastname: Frydman
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D007758:Ear, Inner / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D020440:Gene Duplication; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D034381:Hearing Loss / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D010375:Pedigree; D010766:Phosphorylation; D019108:Tight Junctions / Q000378:metabolism*; D062827:Zonula Occludens-2 Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; C569046:TJP2 protein, human; C569047:Tjp2 protein, mouse; D062827:Zonula Occludens-2 Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3