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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Publication statusAccepted/In press - 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'OSBPL2 mutations impair autophagy and lead to hearing loss, potentially remedied by rapamycin'. Together they form a unique fingerprint.

Cite this