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

Title
Methioninesulfoxide reductase B3 deficiency causes hearing loss due to stereocilia degeneration and apoptotic cell death in cochlear hair cells
Author(s)
김화영권태준[권태준]조현주[조현주]김언경[김언경]이유진오세경[오세경]복진웅[복진웅]배용철[배용철]이준구[이준구]이장우[이장우]류재영[류재영]이상흔[이상흔]이규엽[이규엽]
Keywords
R-SULFOXIDE REDUCTASES; ENDOPLASMIC-RETICULUM; ANTIOXIDANT DEFENSE; KNOCKOUT MOUSE; MAMMALS; IDENTIFICATION; OXIDATION; DISEASES; REPAIR; MSRB1
Issue Date
201403
Publisher
OXFORD UNIV PRESS
Citation
HUMAN MOLECULAR GENETICS, v.23, no.6, pp.1591 - 1601
Abstract
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 MsrB3knockout 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.
URI
http://hdl.handle.net/YU.REPOSITORY/32849http://dx.doi.org/10.1093/hmg/ddt549
ISSN
0964-6906
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의과대학 > 생화학.분자생물학교실 > Articles
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