Mutation of <i>IFNLR1</i>, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss.

Abstract

<b>Background</b> Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. <b>Objectives</b> 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). <b>Methods</b> Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. <i>ifnlr1</i> Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism. <b>Results</b> We identified a cosegregating heterozygous missense mutation, c.296G>A (p.Arg99His) in the gene encoding interferon lambda receptor 1 (<i>IFNLR1</i>) - a protein that functions in the Jak/ STAT pathway- are associated with <i>ADNSHL</i> 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 <i>ifnlr1</i> mRNA. Knockdown of <i>ifnlr1</i> 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. <b>Conclusion</b><i>IFNLR1</i> function is required in the auditory system and that <i>IFNLR1</i> mutations are associated with ADNSHL. To the best of our knowledge, this is the first study implicating an interferon lambda receptor in auditory function.