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

Author:

Li Qing1ORCID,Cui Chong2,Liao Rongyu3,Yin Xidi4,Huang Bowei5,Cheng Yanbo4,Wang Daqi5,Wang Liqin5,Yan Meng3,Zhou Jinan5,Zhao Jingjing5,Tang Wei4,Wang Yingyi6,Wan Xiaohan5,Lv Jun5,Li Jinsong4,Li Huawei2,Shu Yilai2

Affiliation:

1. CAS Center for Excellence in Molecular Cell Science

2. Fudan University Eye Ear Nose and Throat Hospital Department of Ophthalmology

3. IBCB: Shanghai Institute of Biochemistry and Cell Biology

4. Shanghai Institute of Biochemistry: Shanghai Institute of Biochemistry and Cell Biology

5. Fudan University

6. ShanghaiTech University

Abstract

Abstract Mutations 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 formation of intercellular gap junction channels and impairs mechanoelectrical transduction 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.

Publisher

Research Square Platform LLC

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