Heterozygous mutation of Ush1g/Sans in mice causes early-onset progressive hearing loss, which is recovered by reconstituting the strain-specific mutation in Cdh23

被引：21

作者：

Miyasaka, Yuki ^{[1
,3
]}

Shitara, Hiroshi ^{[2
,5
]}

Suzuki, Sari ^{[1
]}

Yoshimoto, Sachi ^{[2
,5
]}

Seki, Yuta ^{[1
]}

Ohshiba, Yasuhiro ^{[1
,3
]}

Okumura, Kazuhiro ^{[6
]}

Taya, Choji ^{[2
]}

Tokano, Hisashi ^{[7
]}

Kitamura, Ken ^{[7
]}

Takada, Toyoyuki ^{[8
]}

Hibino, Hiroshi ^{[4
]}

Shiroishi, Toshihiko ^{[8
]}

Kominami, Ryo ^{[3
]}

Yonekawa, Hiromichi ^{[2
]}

Kikkawa, Yoshiaki ^{[1
,3
]}

机构：

[1] Tokyo Metropolitan Inst Med Sci, Mammalian Genet Project, Tokyo 1568506, Japan

[2] Tokyo Metropolitan Inst Med Sci, Lab Transgen Technol, Tokyo 1568506, Japan

[3] Niigata Univ, Grad Sch Med & Dent Sci, Sch Med, Niigata 9518510, Japan

[4] Niigata Univ, Dept Mol Physiol, Sch Med, Niigata 9518510, Japan

[5] Univ Tsukuba, Grad Sch Life & Environm Sci, Tsukuba, Ibaraki 3058572, Japan

[6] Chiba Canc Ctr Res Inst, Div Oncogen, Canc Genome Ctr, Chiba 2600801, Japan

[7] Tokyo Med & Dent Univ, Dept Otolaryngol, Tokyo 1130034, Japan

[8] Natl Inst Genet, Mammalian Genet Lab, Mishima, Shizuoka 4118540, Japan

来源：

HUMAN MOLECULAR GENETICS | 2016年 / 25卷 / 10期

基金：

日本学术振兴会;

关键词：

COCHLEAR HAIR-CELLS; JACKSON SHAKER MICE; MYOSIN VIIA GENE; USHER-SYNDROME; RECESSIVE DEAFNESS; DBA/2J MICE; INNER-EAR; DIGENIC INHERITANCE; ALLELIC MUTATIONS; C57BL/6J MICE;

D O I：

10.1093/hmg/ddw078

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Most clinical reports have suggested that patients with congenital profound hearing loss have recessive mutations in deafness genes, whereas dominant alleles are associated with progressive hearing loss (PHL). Jackson shaker (Ush1g(js)) is a mouse model of recessive deafness that exhibits congenital profound deafness caused by the homozygous mutation of Ush1g/Sans on chromosome 11. We found that C57BL/6J-Ush1g(js/+) heterozygous mice exhibited early-onset PHL (ePHL) accompanied by progressive degeneration of stereocilia in the cochlear outer hair cells. Interestingly, ePHL did not develop in mutant mice with the C3H/HeN background, thus suggesting that other genetic factors are required for ePHL development. Therefore, we performed classical genetic analyses and found that the occurrence of ePHL in Ush1g(js/+) mice was associated with an interval in chromosome 10 that contains the cadherin 23 gene (Cdh23), which is also responsible for human deafness. To confirm this mutation effect, we generated C57BL/6J-Ush1g(js/+), Cdh23(c.753A/G) double-heterozygous mice by using the CRISPR/Cas9-mediated Cdh23(c.753A > G) knock-in method. The Cdh23(c.753A/G) mice harbored a one-base substitution (A for G), and the homozygous A allele caused moderate hearing loss with aging. Analyses revealed the complete recovery of ePHL and stereocilia degeneration in C57BL/6J-Ush1g(js/+) mice. These results clearly show that the development of ePHL requires at least two mutant alleles of the Ush1g and Cdh23 genes. Our results also suggest that because the SANS and CDH23 proteins form a complex in the stereocilia, the interaction between these proteins may play key roles in the maintenance of stereocilia and the prevention of ePHL.

引用

页码：2045 / 2059

页数：15