The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice

Author:

Li QingORCID,Cui Chong,Liao Rongyu,Yin Xidi,Wang Daqi,Cheng Yanbo,Huang Bowei,Wang Liqin,Yan Meng,Zhou Jinan,Zhao Jingjing,Tang Wei,Wang Yingyi,Wang Xiaohan,Lv Jun,Li Jinsong,Li Huawei,Shu Yilai

Abstract

AbstractMutations in GJB2 (Gap junction protein beta 2) are the most common genetic cause of non-syndromic hereditary deafness in humans, especially the 35delG and 235delC mutations. Owing to the homozygous lethality of Gjb2 mutations in mice, there are currently no perfect mouse models carrying Gjb2 mutations derived from patients for mimicking human hereditary deafness and for unveiling the pathogenesis of the disease. Here, we successfully constructed heterozygous Gjb2+/35delG and Gjb2+/235delC mutant mice through advanced androgenic haploid embryonic stem cell (AG-haESC)-mediated semi-cloning technology, and these mice showed normal hearing at postnatal day (P) 28. A homozygous mutant mouse model, Gjb235delG/35delG, was then generated using enhanced tetraploid embryo complementation, demonstrating that GJB2 plays an indispensable role in mouse placenta development. These mice exhibited profound hearing loss similar to human patients at P14, i.e., soon after the onset of hearing. Mechanistic analyses showed that Gjb2 35delG disrupts the function and formation of intercellular gap junction channels of the cochlea rather than affecting the survival and function of hair cells. Collectively, our study provides ideal mouse models for understanding the pathogenic mechanism of DFNB1A-related hereditary deafness and opens up a new avenue for investigating the treatment of this disease.

Funder

National Natural Science Foundation of China

Innovative Research Group Project of the National Natural Science Foundation of China

the National Key R&D Program of China

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Cellular and Molecular Neuroscience,Pharmacology,Molecular Biology,Molecular Medicine

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