Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss.
Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss.
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IFNLR1（一种干扰素 lambda 受体 1）的突变与常染色体显性非综合征性听力损失有关
DOI：
10.1136/jmedgenet-2017-104954
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发表时间：
2018-05
影响因子：
4
通讯作者：
Dai P
中科院分区：
文献类型：
--
作者：
Gao X;Yuan YY;Lin QF;Xu JC;Wang WQ;Qiao YH;Kang DY;Bai D;Xin F;Huang SS;Qiu SW;Guan LP;Su Y;Wang GJ;Han MY;Jiang Y;Liu HK;Dai P
背景 遗传性感音神经性听力损失是一种遗传异质性疾病。目的 本研究旨在探讨一个患有常染色体显性遗传、非综合征、进行性感音神经性听力损失 (ADNSHL) 的中国大家族中耳聋的遗传病因。方法通过全外显子组测序和连锁分析来鉴定致病突变。通过小鼠免疫染色研究 Ifnlr1 的内耳表达。 ifnlr1 Morpholino 敲低斑马鱼的构建是为了探索耳聋机制。结果 我们在编码干扰素 lambda 受体 1 (IFNLR1)（一种在 Jak/STAT 通路中发挥作用的蛋白质）的基因中发现了一个共分离杂合错义突变 c.296G>A (p.Arg99His)，该突变与 ADNSHL 相关。 ifnlr1 的吗啡啉敲低会导致晚期斑马鱼的毛细胞显着减少和鳔不膨胀，这可以通过注射正常斑马鱼 ifnlr1 mRNA 来逆转。斑马鱼中 ifnlr1 的敲低会导致 Jak1/STAT3 通路中细胞因子受体家族成员 b4 (interleukin-10r2)、jak1、酪氨酸激酶 2、stat3 和 stat5b 在 mRNA 水平上显着上调。结论 IFNLR1 功能是听觉系统所必需的，并且 IFNLR1 突变与 ADNSHL 相关。据我们所知，这是第一项将干扰素 lambda 受体与听觉功能联系起来的研究。
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. Conclusion IFNLR1 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.
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DOI：
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发表时间：
2016-06-07
期刊：
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影响因子：
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DOI：
10.1073/pnas.1402898111
发表时间：
2014-04-08
影响因子：
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