Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51.
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.
Walsh
Tom
T
Department of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195, USA.
Pierce
Sarah B
SB
Lenz
Danielle R
DR
Brownstein
Zippora
Z
Dagan-Rosenfeld
Orit
O
Shahin
Hashem
H
Roeb
Wendy
W
McCarthy
Shane
S
Nord
Alex S
AS
Gordon
Carlos R
CR
Ben-Neriah
Ziva
Z
Sebat
Jonathan
J
Kanaan
Moien
M
Lee
Ming K
MK
Frydman
Moshe
M
King
Mary-Claire
MC
Avraham
Karen B
KB
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
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