Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via sonic hedgehog signaling.

Hairong Shi,Yajie Lu,Jun Yao,Zhibin Chen,Cheng Zhang,Hongshun Wang,Xin Cao,Guangqian Xing,Qinjun Wei

doi:10.1172/jci.insight.149626

Abstract

Defective primary cilia cause a range of diseases called ciliopathies, which include hearing loss (HL). Variants in the human oxysterol-binding protein like 2 (OSBPL2/ORP2) are responsible for autosomal dominant nonsyndromic HL (DFNA67). However, the pathogenesis of OSBPL2 deficiency has not been fully elucidated. In this study, we show that the Osbpl2-KO mice exhibited progressive HL and abnormal cochlear development with defective cilia. Further research revealed that OSBPL2 was located at the base of the kinocilia in hair cells (HCs) and primary cilia in supporting cells (SCs) and functioned in the maintenance of ciliogenesis by regulating the homeostasis of PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) on the cilia membrane. OSBPL2 deficiency led to a significant increase of PI(4,5)P2 on the cilia membrane, which could be partially rescued by the overexpression of INPP5E. In addition, smoothened and GL13, the key molecules in the Sonic Hedgehog (Shh) signaling pathway, were detected to be downregulated in Osbpl2-KO HEI-OC1 cells. Our findings revealed that OSBPL2 deficiency resulted in ciliary defects and abnormal Shh signaling transduction in auditory cells, which helped to elucidate the underlying mechanism of OSBPL2 deficiency in HL.

Highlights

Primary cilia are microtubule-based, antenna-like and nonmotile organelles that protrude from the apical membrane in many cell types [1,2,3,4]
Our findings revealed the potential role of OSBPL2 in the regulation of ciliogenesis in auditory cells and helped to elucidate the pathogenesis of OSBPL2 deficiency implicated in Hearing loss (HL)
The structure of cilia can be classified into three subdomains: the intracellular basal body (BB), which controls cilium formation; the extracellular axoneme, which generates force; and the transition zone (TZ), which bridges cilia [40, 41]

Summary

Introduction

Primary cilia are microtubule-based, antenna-like and nonmotile organelles that protrude from the apical membrane in many cell types [1,2,3,4]. Auditory hair cells (HCs) are mechanoreceptors of the auditory system and each HC has an apically located hair bundle made up of a single kinocilium and many stereocilia [11]. Hearing loss (HL) in relation to HCs’ ciliary defects is considered to be a kind of ciliopathy [12]. Studies on cilia-related HL have mainly been focused on stereocilia, which are the key organelles responsible for the conversion of mechanical energy into electrical signals [13,14,15]. Kinocilia have drawn a growing interest due to their important roles in the development of hair bundle polarity and the maintenance of normal hearing [16, 17]. Webb et al reported that the loss of kinociliary links was considered as a cause of abnormal polarity of hair bundles in PCDH15-CD2-

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