单位：[1]Department of Otorhinolaryngology, China-Japan Friendship Hospital, Beijing 1000292, China [2]Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou 5100063, China [3]State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 1001014, China [4]Bioinformatics Section, Angen Gene Medicine Technology, Beijing 1001765, China [5]VitroVivo Biotech LLC, Rockville, MD 208506, USA [6]Experimental Medicine Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 208927, USA [7]Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA
Hereditary hearing loss is a highly genetically heterogeneous disorder. More than 150 genes have been identified to link to human non-syndromic hearing impairment. To identify genetic mutations and underlying molecular mechanisms in affected individuals and families with congenital hearing loss, we recruited a cohort of 389 affected individuals in 354 families for whole-exome sequencing analysis. In this study, we report a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in the OXR1 gene, which was identified in a 4-year-old girl with sensorineural hearing loss. OXR1 encodes Oxidation Resistance 1 and is evolutionarily conserved from zebrafish to human. We found that the ortholog oxr1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL) in zebrafish. Knockdown of oxr1b in zebrafish resulted in a significant developmental defect of SAG and pLL. This phenotype can be rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs. OXR1-associated pathway analysis revealed that mutations of TBC1D24, a TLDc-domain-containing homolog gene of OXR1, have previously been identified in patients with hearing loss. Interestingly, mutations or knockout of OXR1 interacting molecules such as ATP6V1B1 and ESR1 are also associated with hearing loss in patients or animal models, hinting an important role of OXR1 and associated partners in cochlear development and hearing function.
基金：
Audiology Development Foundation of China [N053100000500017757XA19013]; National Natural Science Foundation of China [32025014, 31872838]; National Key Research and Development Program of China 671 [2018YFA0800200, 2020YFA0804000]
第一作者单位：[1]Department of Otorhinolaryngology, China-Japan Friendship Hospital, Beijing 1000292, China
共同第一作者：
通讯作者：
通讯机构：[6]Experimental Medicine Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 208927, USA [7]Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA
推荐引用方式(GB/T 7714)：
Li Yuan,Ning Guozhu,Kang Baoling,et al.A novel recessive mutation in OXR1 is identified in patient with hearing loss recapitulated by the knockdown zebrafish[J].HUMAN MOLECULAR GENETICS.2022,doi:10.1093/hmg/ddac229.
APA：
Li, Yuan,Ning, Guozhu,Kang, Baoling,Zhu, Jinwen,Wang, Xiao-Yang...&Cai, Tao.(2022).A novel recessive mutation in OXR1 is identified in patient with hearing loss recapitulated by the knockdown zebrafish.HUMAN MOLECULAR GENETICS,,
MLA：
Li, Yuan,et al."A novel recessive mutation in OXR1 is identified in patient with hearing loss recapitulated by the knockdown zebrafish".HUMAN MOLECULAR GENETICS .(2022)
生物学