Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss.
- Gao, X., Yuan, Y.Y., Lin, Q.F., Xu, J.C., Wang, W.Q., Qiao, Y.H., Kang, D.Y., Bai, D., Xin, F., Huang, S.S., Qiu, S.W., Guan, L.P., Su, Y., Wang, G.J., Han, M.Y., Jiang, Y., Liu, H.K., Dai, P.
- Journal of Medical Genetics 55(5): 298-306 (Journal)
- Registered Authors
- ADNSHL, IFNLR1, JAK/STAT pathway, deafness gene
- MeSH Terms
- Gene Knockdown Techniques
- Genetic Linkage
- Genetic Predisposition to Disease*
- Hearing Loss, Sensorineural/genetics*
- Hearing Loss, Sensorineural/physiopathology
- Janus Kinase 1/genetics
- Mutation, Missense/genetics
- Receptors, Cytokine/genetics*
- Receptors, Interferon/genetics*
- STAT3 Transcription Factor/genetics
- Signal Transduction
- Whole Exome Sequencing
- 29453195 Full text @ J. Med. Genet.
Gao, X., Yuan, Y.Y., Lin, Q.F., Xu, J.C., Wang, W.Q., Qiao, Y.H., Kang, D.Y., Bai, D., Xin, F., Huang, S.S., Qiu, S.W., Guan, L.P., Su, Y., Wang, G.J., Han, M.Y., Jiang, Y., Liu, H.K., Dai, P. (2018) Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss.. Journal of Medical Genetics. 55(5):298-306.
Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic, progressive sensorineural hearing loss (ADNSHL). Methods Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. ifnlr1 Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism. Results We identified a cosegregating heterozygous missense mutation, c.296G>A (p.Arg99His) in the gene encoding interferon lambda receptor 1 (IFNLR1) - a protein that functions in the Jak/ STAT pathway- are associated with ADNSHL Morpholino knockdown of ifnlr1 leads to a significant decrease in hair cells and non-inflation of the swim bladder in late-stage zebrafish, which can be reversed by injection with normal Zebrafish ifnlr1 mRNA. Knockdown of ifnlr1 in zebrafish causes significant upregulation of cytokine receptor family member b4 (interleukin-10r2), jak1, tyrosine kinase 2, stat3, and stat5b in the Jak1/STAT3 pathway at the mRNA level. ConclusionIFNLR1 function is required in the auditory system and that IFNLR1 mutations are associated with ADNSHL. To the best of our knowledge, this is the first study implicating an interferon lambda receptor in auditory function.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes