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.