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Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via sonic hedgehog signaling.
- Source :
-
JCI insight [JCI Insight] 2022 Feb 22; Vol. 7 (4). Date of Electronic Publication: 2022 Feb 22. - Publication Year :
- 2022
-
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.
- Subjects :
- Animals
DNA Mutational Analysis
Disease Models, Animal
Hair Cells, Auditory metabolism
Hearing Loss metabolism
Hearing Loss pathology
Hedgehog Proteins metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Receptors, Steroid metabolism
Signal Transduction
DNA genetics
Hair Cells, Auditory pathology
Hearing Loss genetics
Hedgehog Proteins genetics
Mutation
Receptors, Steroid genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 7
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 35041619
- Full Text :
- https://doi.org/10.1172/jci.insight.149626