Null Mutation of the Fascin2 Gene by TALEN Leading to Progressive Hearing Loss and Retinal Degeneration in C57BL/6J Mice

G3: Genes, Genomes, Genetics

Yi Xie^1,3¹  Mengmeng Zhao^1,3²  Ping Li^1³  Xiang Liu^1,2⁴ 

[1] Department of Biochemistry and Molecular Biology, Binzhou Medical, University, 346 Guanhai Road, Yantai 264003, Shandong, P. R. China^3;Department of Human Anatomy and Histology and Embryology, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, Shandong, P. R. China^2;Department of Otorhinolaryngology-Head and Neck Surgery, Yuhuangding Hospital, 20 East Yuhuangding Road, Yantai 264000, Shandong, P.R. China^4;Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical, University, 346 Guanhai Road, Yantai 264003, Shandong, P. R. China^1

关键词: Fascin2;    mutation;    TALEN;    hearing loss;    hair cell;    retinitis pigmentosa;   

DOI  :  10.1534/g3.118.200405

学科分类：生物科学（综合）

来源: Genetics Society of America

【 摘 要 】

Fascin2 (FSCN2) is an actin cross-linking protein that is mainly localized in retinas and in the stereocilia of hair cells. Earlier studies showed that a deletion mutation in human FASCIN2 ( FSCN2 ) gene could cause autosomal dominant retinitis pigmentosa. Recent studies have indicated that a missense mutation in mouse Fscn2 gene (R109H) can contribute to the early onset of hearing loss in DBA/2J mice. To explore the function of the gene, Fscn2 was knocked out using TALEN (transcription activator-like effector nucleases) on the C57BL/6J background. Four mouse strains with deletions of 1, 4, 5, and 41 nucleotides in the target region of Fscn2 were developed. F1 heterozygous ( Fscn2^+/− ) mice carrying the same deletion of 41 nucleotides were mated to generate the Fscn2^−/− mice. As a result, the Fscn2^−/− mice showed progressive hearing loss, as measured in the elevation of auditory brainstem-response thresholds. The hearing impairment began at age 3 weeks at high-stimulus frequencies and became most severe at age 24 weeks. Moreover, degeneration of hair cells and loss of stereocilia were remarkable in Fscn2^−/− mice, as revealed by F-actin staining and scanning electron microscopy. Furthermore, compared to the controls, the Fscn2^−/− mice displayed significantly lower electroretinogram amplitudes and thinner retinas at 8, 16, and 24 weeks. These results demonstrate that, in C57BL/6Jmice, Fscn2 is essential for maintaining ear and eye function and that a null mutation of Fscn2 leads to progressive hearing loss and retinal degeneration.

【 授权许可】

CC BY