ZFIN ID: ZDB-PUB-180223-33
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.
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.