Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice

被引:232
作者
Lee, MP
Ravenel, JD
Hu, RJ
Lustig, LR
Tomaselli, G
Berger, RD
Brandenburg, SA
Litzi, TJ
Bunton, TE
Limb, C
Francis, H
Gorelikow, M
Gu, H
Washington, K
Argani, P
Goldenring, JR
Coffey, RJ
Feinberg, AP
机构
[1] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Inst Geriat Med, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA
[4] NIAID, Immunol Lab, Rockville, MD USA
[5] Johns Hopkins Univ, Sch Med, Dept Otorhinolaryngol, Baltimore, MD USA
[6] Johns Hopkins Univ, Sch Med, Dept Comparat Med, Baltimore, MD USA
[7] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN USA
[8] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD USA
[9] Med Coll Georgia, Inst Mol Med & Genet, Augusta, GA 30912 USA
[10] Vet Affairs Med Ctr, Augusta, GA USA
关键词
D O I
10.1172/JCI10897
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The K nu LQT1 gene encodes a voltage-gated potassium channel. Mutations in K nu LQT1 underlie the dominantly transmitted Ward-Romano long QT syndrome, which causes cardiac arrhythmia, and the recessively transmitted Jervell and Lange-Nielsen syndrome, which causes both cardiac arrhythmia and congenital deafness. K nu LQT1 is also disrupted by balanced germline chromosomal rearrangements in patients with Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth and cancer. Because of the diverse human disorders and organ systems affected by this gene, we developed an animal model by inactivating the murine K nu lqt1. No electrocardiographic abnormalities were observed. However, homozygous mice exhibited complete deafness, as well as circular movement and repetitive falling, suggesting imbalance. Histochemical study revealed severe anatomic disruption of the cochlear and vestibular end organs, suggesting that K nu lqt1 is essential for normal development of the inner ear. Surprisingly, homozygous mice also displayed threefold enlargement by weight of the stomach resulting from mucous neck cell hyperplasia. Finally, there were no features of BWS, suggesting that K nu lqt1 is not responsible for BWS.
引用
收藏
页码:1447 / 1455
页数:9
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