A novel recessive mutation in OXR1 is identified in patient with hearing loss recapitulated by the knockdown zebrafish
Open Access
- 20 September 2022
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 32 (5), 764-772
- https://doi.org/10.1093/hmg/ddac229
Abstract
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.Funding Information
- Audiology Development Foundation of China (NO53100000500017757XA19013)
- National Natural Science Foundation of China (32025014, 31872838)
- National Key Research and Development Program of China (2018YFA0800200, 2020YFA0804000)
- ANGEN Inc.
- NIH
This publication has 43 references indexed in Scilit:
- Whole-Exome Sequencing Efficiently Detects Rare Mutations in Autosomal Recessive Nonsyndromic Hearing LossPLOS ONE, 2012
- A Spatial and Temporal Gradient of Fgf Differentially Regulates Distinct Stages of Neural Development in the Zebrafish Inner EarPLoS Genetics, 2012
- Structural/functional analysis of the human OXR1 protein: identification of exon 8 as the anti-oxidant encoding functionBMC Molecular Biology, 2012
- Oxr1 Is Essential for Protection against Oxidative Stress-Induced NeurodegenerationPLoS Genetics, 2011
- Hearing loss: a common disorder caused by many rare allelesAnnals of the New York Academy of Sciences, 2010
- Smad2/3 activities are required for induction and patterning of the neuroectoderm in zebrafishDevelopmental Biology, 2009
- Inner ear pathology and loss of hearing in estrogen receptor-β deficient miceJournal of Endocrinology, 2009
- Regulation of cell fate in the sensory epithelia of the inner earNature Reviews Neuroscience, 2006
- Deafness Genes and Their Diagnostic ApplicationsAudiology and Neurotology, 2003
- Stages of embryonic development of the zebrafishDevelopmental Dynamics, 1995