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 language | English (US) |
|---|---|
| Pages (from-to) | 101-109 |
| Number of pages | 9 |
| Journal | American Journal of Human Genetics |
| Volume | 87 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 9 2010 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
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.
In: American Journal of Human Genetics, Vol. 87, No. 1, 09.07.2010, p. 101-109.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51
AU - Walsh, Tom
AU - Pierce, Sarah B.
AU - Lenz, Danielle R.
AU - Brownstein, Zippora
AU - Dagan-Rosenfeld, Orit
AU - Shahin, Hashem
AU - Roeb, Wendy
AU - McCarthy, Shane
AU - Nord, Alexander
AU - Gordon, Carlos R.
AU - Ben-Neriah, Ziva
AU - Sebat, Jonathan
AU - Kanaan, Moien
AU - Lee, Ming K.
AU - Frydman, Moshe
AU - King, Mary Claire
AU - Avraham, Karen B.
PY - 2010/7/9
Y1 - 2010/7/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2010.05.011
DO - 10.1016/j.ajhg.2010.05.011
M3 - Article
VL - 87
SP - 101
EP - 109
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -