title: Heterozygous mutation of Ush1g/Sans in mice causes early-onset progressive hearing loss, which is recovered by reconstituting the strain-specific mutation in Cdh23.
abstract: 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 (Ush1gjs) 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-Ush1gjs/+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 Ush1gjs/+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-Ush1gjs/+, Cdh23c.753A/Gdouble-heterozygous mice by using the CRISPR/Cas9-mediated Cdh23c.753A>Gknock-in method. The Cdh23c.753A/Gmice 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-Ush1gjs/+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.
authors.affiliation: Mammalian Genetics Project, Graduate School of Medical and Dental Sciences.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miyasaka
authors.affiliation: Laboratory for Transgenic Technology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shitara
authors.affiliation: Mammalian Genetics Project.
authors.forename: Sari
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Laboratory for Transgenic Technology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan.
authors.forename: Sachi
authors.initials: S
authors.lastname: Yoshimoto
authors.affiliation: Mammalian Genetics Project.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Seki
authors.affiliation: Mammalian Genetics Project, Graduate School of Medical and Dental Sciences.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ohshiba
authors.affiliation: Division of Oncogenomics, Cancer Genome Center, Chiba Cancer Center Research Institute, Chiba 260-0801, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Laboratory for Transgenic Technology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Choji
authors.initials: C
authors.lastname: Taya
authors.affiliation: Department of Otolaryngology, Tokyo Medical and Dental University, Tokyo 113-0034, Japan and.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tokano
authors.affiliation: Department of Otolaryngology, Tokyo Medical and Dental University, Tokyo 113-0034, Japan and.
authors.forename: Ken
authors.initials: K
authors.lastname: Kitamura
authors.affiliation: Mammalian Genetics Laboratory, National Institute of Genetics, Mishima 411-8540, Japan.
authors.forename: Toyoyuki
authors.initials: T
authors.lastname: Takada
authors.affiliation: Department of Molecular Physiology, Niigata University School of Medicine, Niigata 951-8510, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hibino
authors.affiliation: Mammalian Genetics Laboratory, National Institute of Genetics, Mishima 411-8540, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Shiroishi
authors.affiliation: Graduate School of Medical and Dental Sciences.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kominami
authors.affiliation: Laboratory for Transgenic Technology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yonekawa
authors.affiliation: Mammalian Genetics Project, Graduate School of Medical and Dental Sciences, kikkawa-ys@igakuken.or.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kikkawa
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D015820:Cadherins / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D004195:Disease Models, Animal; D018072:Hair Cells, Auditory, Outer / Q000473:pathology; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D059547:Stereocilia / Q000473:pathology
chemical_list: D015820:Cadherins; C499091:Cdh23 protein, mouse; D009419:Nerve Tissue Proteins; C477451:Sans protein, mouse