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OSBPL2 mutations impair autophagy and lead to hearing loss, potentially remedied by rapamycin

 Young Ik Koh  ;  Kyung Seok Oh  ;  Jung Ah Kim  ;  Byunghwa Noh  ;  Hye Ji Choi  ;  Sun Young Joo  ;  John Hoon Rim  ;  Hye-Youn Kim  ;  Dong Yun Kim  ;  Seyoung Yu  ;  Da Hye Kim  ;  Sang-Guk Lee  ;  Jinsei Jung  ;  Jae Young Choi  ;  Heon Yung Gee 
 AUTOPHAGY, Vol.18(11) : 2593-2614, 2022-11 
Journal Title
Issue Date
Animals ; Autophagy / genetics ; Deafness* / genetics ; HEK293 Cells ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mutant Proteins ; Mutation / genetics ; Receptors, Steroid* / genetics ; Sirolimus / pharmacology
Autophagy ; DFNA67 ; OSBPL2 ; hearing loss ; rapamycin
Intracellular accumulation of mutant proteins causes proteinopathies, which lack targeted therapies. Autosomal dominant hearing loss (DFNA67) is caused by frameshift mutations in OSBPL2. Here, we show that DFNA67 is a toxic proteinopathy. Mutant OSBPL2 accumulated intracellularly and bound to macroautophagy/autophagy proteins. Consequently, its accumulation led to defective endolysosomal homeostasis and impaired autophagy. Transgenic mice expressing mutant OSBPL2 exhibited hearing loss, but osbpl2 knockout mice or transgenic mice expressing wild-type OSBPL2 did not. Rapamycin decreased the accumulation of mutant OSBPL2 and partially rescued hearing loss in mice. Rapamycin also partially improved hearing loss and tinnitus in individuals with DFNA67. Our findings indicate that dysfunctional autophagy is caused by mutant proteins in DFNA67; hence, we recommend rapamycin for DFNA67 treatment.Abbreviations: ABR: auditory brainstem response; ACTB: actin beta; CTSD: cathepsin D; dB: decibel; DFNA67: deafness non-syndromic autosomal dominant 67; DPOAE: distortion product otoacoustic emission; fs: frameshift; GFP: green fluorescent protein; HsQ53R-TG: human p.Q53Rfs*100-transgenic: HEK 293: human embryonic kidney 293; HFD: high-fat diet; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NSHL: non-syndromic hearing loss; OHC: outer hair cells; OSBPL2: oxysterol binding protein-like 2; SEM: scanning electron microscopy; SGN: spiral ganglion neuron; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TG: transgenic; WES: whole-exome sequencing; YUHL: Yonsei University Hearing Loss; WT: wild-type.
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1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hye-Youn(김혜연) ORCID logo https://orcid.org/0000-0003-2090-6427
Lee, Sang-Guk(이상국) ORCID logo https://orcid.org/0000-0003-3862-3660
Rim, John Hoon(임정훈) ORCID logo https://orcid.org/0000-0001-6825-8479
Jung, Jinsei(정진세) ORCID logo https://orcid.org/0000-0003-1906-6969
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
Choi, Jae Young(최재영) ORCID logo https://orcid.org/0000-0001-9493-3458
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