Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via sonic hedgehog signaling
Hairong Shi, … , Qinjun Wei, Xin Cao
Hairong Shi, … , Qinjun Wei, Xin Cao
Published January 18, 2022
Citation Information: JCI Insight. 2022;7(4):e149626. https://doi.org/10.1172/jci.insight.149626.
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Research Article Genetics Otology

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

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.

Authors

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

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Figure 3

OSBPL2 was localized at the base of cilia and regulated the ciliary length.

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OSBPL2 was localized at the base of cilia and regulated the ciliary leng...
(A) Immunofluorescence staining of the basal turn of sensory epithelium in P3 Osbpl2–/– and WT mice with anti-acetylated tubulin (red), anti-OSBPL2 (green), and phalloidin (blue). Scale bars: 5μm. (B) Immunofluorescence staining of Osbpl2–/– and WT HEI-OC1 cells with anti-acetylated tubulin (green), anti-OSBPL2 (red), anti–gamma-tubulin (grey), and DAPI (blue). Scale bar: 5 μm. (C) Immunofluorescence staining of Osbpl2–/– and WT HEI-OC1 cells with anti-acetylated tubulin (red in cilia), anti–gamma-tubulin (green in ciliary base bodies), and DAPI (blue in nuclei). (D) The length of cilia in Osbpl2–/– and WT HEI-OC1 cells (50 cells per genotype, each dot represents a cell; *P < 0.05; **P < 0.01 by 2-tailed Student’s t test). (E) The proportion of ciliated cells in Osbpl2–/– and WT HEI-OC1 cells (50 cells per genotype, each dot represents the proportion of ciliated cells in a microscope field; ns: not significant by 2-tailed Student’s t test). Scale bar: 5 μm.