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Methionine sulfoxide reductase B3 deficiency causes hearing loss due to stereocilia degeneration and apoptotic cell death in cochlear hair cells

 Tae-Jun Kwon  ;  Hyun-Ju Cho  ;  Un-Kyung Kim  ;  Eujin Lee  ;  Se-Kyung Oh  ;  Jinwoong Bok  ;  Yong Chul Bae  ;  Jun-Koo Yi  ;  Jang Woo Lee  ;  Zae-Young Ryoo  ;  Sang Heun Lee  ;  Kyu-Yup Lee  ;  Hwa-Young Kim 
 HUMAN MOLECULAR GENETICS, Vol.23(6) : 1591-1601, 2014 
Journal Title
Issue Date
Animals ; Apoptosis ; Cochlea/pathology* ; Disease Models, Animal ; Gene Expression Regulation, Developmental ; Hair Cells, Auditory/pathology ; Hearing Loss/enzymology ; Hearing Loss/genetics* ; Hearing Loss/pathology* ; Humans ; Methionine Sulfoxide Reductases/genetics* ; Methionine Sulfoxide Reductases/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Electron, Scanning ; Microscopy, Electron, Transmission ; Stereocilia/metabolism ; Stereocilia/pathology*
methionine ; cell death ; genes ; auditory hair cell ; heterozygote ; homozygote ; in situ nick-end labeling ; inner ear ; mice ; knockout ; oxidoreductase ; sulfoxides ; enzymes ; hearing impairment ; stereocilium ; tissue degeneration ; caspase-3 ; profound hearing loss
Methionine sulfoxide reductase B3 (MsrB3) is a protein repair enzyme that specifically reduces methionine-R-sulfoxide to methionine. A recent genetic study showed that the MSRB3 gene is associated with autosomal recessive hearing loss in human deafness DFNB74. However, the precise role of MSRB3 in the auditory system and the pathogenesis of hearing loss have not yet been determined. This work is the first to generate MsrB3 knockout mice to elucidate the possible pathological mechanisms of hearing loss observed in DFNB74 patients. We found that homozygous MsrB3−/− mice were profoundly deaf and had largely unaffected vestibular function, whereas heterozygous MsrB3+/− mice exhibited normal hearing similar to that of wild-type mice. The MsrB3 protein is expressed in the sensory epithelia of the cochlear and vestibular tissues, beginning at E15.5 and E13.5, respectively. Interestingly, MsrB3 is densely localized at the base of stereocilia on the apical surface of auditory hair cells. MsrB3 deficiency led to progressive degeneration of stereociliary bundles starting at P8, followed by a loss of hair cells, resulting in profound deafness in MsrB3−/− mice. The hair cell loss appeared to be mediated by apoptotic cell death, which was measured using TUNEL and caspase 3 immunocytochemistry. Taken together, our data suggest that MsrB3 plays an essential role in maintaining the integrity of hair cells, possibly explaining the pathogenesis of DFNB74 deafness in humans caused by MSRB3 deficiency.
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1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
Yonsei Authors
Bok, Jin Woong(복진웅) ORCID logo https://orcid.org/0000-0003-1958-1872
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