Oxysterol binding protein like 2(OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causal gene in our previous work. To resemble the phenotypic features of ...Oxysterol binding protein like 2(OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causal gene in our previous work. To resemble the phenotypic features of OSBPL2 mutation in animal models and elucidate the potential genotypephenotype associations, the OSBPL2-disrupted Bama miniature(BM) pig model was constructed using CRISPR/Cas9-mediated gene editing, somatic cell nuclear transfer(SCNT) and embryo transplantation approaches, and then subjected to phenotypic characterization of auditory function and serum lipid profiles. The OSBPL2-disrupted pigs displayed progressive hearing loss(HL) with degeneration/apoptosis of cochlea hair cells(HCs) and morphological abnormalities in HC stereocilia, as well as hypercholesterolaemia. High-fat diet(HFD) feeding aggravated the development of HL and led to more severe hypercholesterolaemia. The dual phenotypes of progressive HL and hypercholesterolaemia resembled in OSBPL2-disrupted pigs confirmed the implication of OSBPL2 mutation in nonsydromic hearing loss(NSHL) and contributed to the potential linkage between auditory dysfunction and dyslipidaemia/hypercholesterolaemia.展开更多
A mutation in oxysterol-binding protein-like 2(OSBPL2)has been identified as the genetic cause of autosomal dominant nonsyndromic hearing loss(DFNA67,Online Mendelian Inheritance in Man No.616340).However,the pathogen...A mutation in oxysterol-binding protein-like 2(OSBPL2)has been identified as the genetic cause of autosomal dominant nonsyndromic hearing loss(DFNA67,Online Mendelian Inheritance in Man No.616340).However,the pathogenesis of the OSBPL2 mutation in DFNA remains unclear.Our previous work showed that Osbpl2 deficiency impaired cell adhesion in auditory HEI-OC1 cells.In addition,loss of hair cells(HCs)and morphological abnormalities of HC stereocilia were detected in OSBPL2-knockout pigs,suggesting that OSBPL2 plays an important role in regulating the actin cytoskeleton in auditory cells.In the present study,we found that Osbpl2 deficiency inhibited the Rho/ROCK2 signaling pathway and downregulated phosphorylated ezrin-radixinmoesin(p-ERM),resulting in abnormal F-actin morphology in HEI-OC1 cells and stereociliary defects in mouse HCs.The present study demonstrates the underlying mechanism of OSBPL2 in regulating the actin cytoskeleton in HCs,contributing to a deeper understanding of the pathogenesis of OSBPL2 mutations in DFNA.展开更多
基金supported by grants from the National Natural Science Foundation of China (81771000 and 31571302)the Key Research and Development Program of Jiangsu Province (Social Development: BE2016762)+2 种基金the Key Project of Science and Technology Innovation of Nanjing Medical University (2017NJMUCX001)grants from the China Postdoctoral Science Foundation (2016M600431)the Jiangsu Planned Projects for Postdoctoral Research Funds (1601071B)
文摘Oxysterol binding protein like 2(OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causal gene in our previous work. To resemble the phenotypic features of OSBPL2 mutation in animal models and elucidate the potential genotypephenotype associations, the OSBPL2-disrupted Bama miniature(BM) pig model was constructed using CRISPR/Cas9-mediated gene editing, somatic cell nuclear transfer(SCNT) and embryo transplantation approaches, and then subjected to phenotypic characterization of auditory function and serum lipid profiles. The OSBPL2-disrupted pigs displayed progressive hearing loss(HL) with degeneration/apoptosis of cochlea hair cells(HCs) and morphological abnormalities in HC stereocilia, as well as hypercholesterolaemia. High-fat diet(HFD) feeding aggravated the development of HL and led to more severe hypercholesterolaemia. The dual phenotypes of progressive HL and hypercholesterolaemia resembled in OSBPL2-disrupted pigs confirmed the implication of OSBPL2 mutation in nonsydromic hearing loss(NSHL) and contributed to the potential linkage between auditory dysfunction and dyslipidaemia/hypercholesterolaemia.
基金financially supported by the National Natural Science Foundation of China(Grant Nos.82071052 to J.Y.and 81771000 to X.C.)。
文摘A mutation in oxysterol-binding protein-like 2(OSBPL2)has been identified as the genetic cause of autosomal dominant nonsyndromic hearing loss(DFNA67,Online Mendelian Inheritance in Man No.616340).However,the pathogenesis of the OSBPL2 mutation in DFNA remains unclear.Our previous work showed that Osbpl2 deficiency impaired cell adhesion in auditory HEI-OC1 cells.In addition,loss of hair cells(HCs)and morphological abnormalities of HC stereocilia were detected in OSBPL2-knockout pigs,suggesting that OSBPL2 plays an important role in regulating the actin cytoskeleton in auditory cells.In the present study,we found that Osbpl2 deficiency inhibited the Rho/ROCK2 signaling pathway and downregulated phosphorylated ezrin-radixinmoesin(p-ERM),resulting in abnormal F-actin morphology in HEI-OC1 cells and stereociliary defects in mouse HCs.The present study demonstrates the underlying mechanism of OSBPL2 in regulating the actin cytoskeleton in HCs,contributing to a deeper understanding of the pathogenesis of OSBPL2 mutations in DFNA.
