A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs

被引：36

作者：

Han, F. ^{[1
]}

Yu, H. ^{[1
]}

Tian, C. ^{[1
]}

Chen, H. E. ^{[1
]}

Benedict-Alderfer, C. ^{[1
]}

Zheng, Y. ^{[1
]}

Wang, Q. ^{[1
]}

Han, X. ^{[1
]}

Zheng, Q. Y. ^{[1
,2
,3
]}

机构：

[1] Case Western Reserve Univ, Dept Otolaryngol HNS, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA

[3] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA

来源：

PHARMACOGENOMICS JOURNAL | 2012年 / 12卷 / 01期

关键词：

mouse model; Cdh23; mutation; hearing loss; apoptosis; Z-VAD-FMK; SYNDROME TYPE 1D; USHER-SYNDROME; INBRED STRAINS; HAIR-CELLS; NONSYNDROMIC DEAFNESS; CADHERIN GENE; TIP-LINK; MICE; MUTATIONS; APOPTOSIS;

D O I：

10.1038/tpj.2010.60

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We report a novel mutation (erlong, erl) of the cadherin 23 (Cdh23) gene in a mouse model for DFNB12 characterized by progressive hearing loss beginning from postnatal day 27 (P27). Genetic and sequencing analysis revealed a 2081 >C transition causing an amino-acid substitution (70S-P). Caspase expression was upregulated in mutant inner ears. Hearing was preserved (up to 35-dB improvement) in pan-caspase inhibitor Z-VAD-FMK-treated mutants compared with untreated mutants (P < 0.05). Outer hair cell (OHC) loss in the cochleae of Z-VAD-FMK-treated mutants was significantly reduced compared with those of untreated mice. Thus, the en l mutation can lead to hearing loss through apoptosis. This is the first genetic mouse model of hearing loss shown to respond to otoprotective drug therapy. The short interval from initial hearing loss to deafness (P27-P90) makes this model ideal for screening and validating otoprotective drugs. The Pharmacogenomics Journal (2012) 1 2, 30-44; doi:10.1038/tpj.2010.60; published online 20 July 2010

引用

页码：30 / 44

页数：15

共 43 条

[1] Interactions in the network of Usher syndrome type 1 proteins [J].

Adato, A ;

Michel, V ;

Kikkawa, Y ;

Reiners, J ;

Alagramam, KN ;

Weil, D ;

Yonekawa, H ;

Wolfrum, U ;

El-Amraoui, A ;

Petit, C .

HUMAN MOLECULAR GENETICS, 2005, 14 (03) :347-356

[2] CDH23 mutation and phenotype heterogeneity:: A profile of 107 diverse families with Usher syndrome and nonsyndromic deafness [J].

Astuto, LM ;

Bork, JM ;

Weston, MD ;

Askew, JW ;

Fields, RR ;

Orten, DJ ;

Ohliger, SJ ;

Riazuddin, S ;

Morell, RJ ;

Khan, S ;

Riazuddin, S ;

Kremer, H ;

van Hauwe, P ;

Moller, CG ;

Cremers, CWRJ ;

Ayuso, C ;

Heckenlively, JR ;

Rohrschneider, K ;

Spandau, U ;

Greenberg, J ;

Ramesar, R ;

Reardon, W ;

Bitoun, P ;

Millan, J ;

Legge, R ;

Friedman, TB ;

Kimberling, WJ .

AMERICAN JOURNAL OF HUMAN GENETICS, 2002, 71 (02) :262-275

[3] Disruption of the mouse μ-calpain gene reveals an essential role in platelet function [J].

Azam, M ;

Andrabi, SS ;

Sahr, KE ;

Kamath, L ;

Kuliopulos, A ;

Chishti, AH .

MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (06) :2213-2220

[4] Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D [J].

Bolz, H ;

von Brederlow, B ;

Ramírez, A ;

Bryda, EC ;

Kutsche, K ;

Nothwang, HG ;

Seeliger, M ;

Cabrera, MDS ;

Vila, MC ;

Molina, OP ;

Gal, A ;

Kubisch, C .

NATURE GENETICS, 2001, 27 (01) :108-112

[5] Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23 [J].

Bork, JM ;

Peters, LM ;

Riazuddin, S ;

Bernstein, SL ;

Ahmed, ZM ;

Ness, SL ;

Polomeno, R ;

Ramesh, A ;

Schloss, M ;

Srisailpathy, CRS ;

Wayne, S ;

Bellman, S ;

Desmukh, D ;

Ahmed, Z ;

Khan, SN ;

Kaloustian, VMD ;

Li, XC ;

Lalwani, A ;

Riazuddin, S ;

Bitner-Glindzicz, M ;

Nance, WE ;

Liu, XZ ;

Wistow, G ;

Smith, RJH ;

Griffith, AJ ;

Wilcox, ER ;

Friedman, TB ;

Morell, RJ .

AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 68 (01) :26-37

[6] A high-resolution genetic map around waltzer on mouse Chromosome 10 and identification of a new allele of waltzer [J].

Bryda, EC ;

Ling, H ;

Flaherty, L .

MAMMALIAN GENOME, 1997, 8 (01) :1-4

[7] Protection against cisplatin-induced ototoxicity by adeno-associated virus-mediated delivery of the X-linked inhibitor of apoptosis protein is not dependent on caspase inhibition [J].

Chan, Dylan K. ;

Lieberman, David M. ;

Musatov, Sergei ;

Goldfein, Joshua A. ;

Selesnick, Samuel H. ;

Kaplitt, Michael G. .

OTOLOGY & NEUROTOLOGY, 2007, 28 (03) :417-425

[8] Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease [J].

Chen, M ;

Ona, VO ;

Li, MW ;

Ferrante, RJ ;

Fink, KB ;

Zhu, S ;

Bian, J ;

Guo, L ;

Farrell, LA ;

Hersch, SM ;

Hobbs, W ;

Vonsattel, JP ;

Cha, JHJ ;

Friedlander, RM .

NATURE MEDICINE, 2000, 6 (07) :797-+

[9] Caspase-activation pathways in apoptosis and immunity [J].

Creagh, EM ;

Conroy, H ;

Martin, SJ .

IMMUNOLOGICAL REVIEWS, 2003, 193 (01) :10-21

[10] Mutations in the calcium-binding motifs of CDH23 and the 35delG mutation in GJB2 cause hearing loss in one family [J].

de Brouwer, APM ;

Pennings, RJE ;

Roeters, M ;

Van Hauwe, P ;

Astuto, LM ;

Hoefsloot, LH ;

Huygen, PLM ;

van den Helm, B ;

Deutman, AF ;

Bork, JM ;

Kimberling, WJ ;

Cremers, FPM ;

Cremers, CWRJ ;

Kremer, H .

HUMAN GENETICS, 2003, 112 (02) :156-163

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