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Novel disease loci
Original Article
Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss
  1. Xue Gao1,2,
  2. Yong-Yi Yuan1,
  3. Qiong-Fen Lin3,4,
  4. Jin-Cao Xu2,
  5. Wei-Qian Wang2,
  6. Yue-Hua Qiao5,
  7. Dong-Yang Kang1,
  8. Dan Bai6,
  9. Feng Xin7,
  10. Sha-Sha Huang1,
  11. Shi-Wei Qiu1,5,
  12. Li-Ping Guan3,4,
  13. Yu Su1,
  14. Guo-Jian Wang1,
  15. Ming-Yu Han1,
  16. Yi Jiang1,8,
  17. Han-Kui Liu3,4,
  18. Pu Dai1
  1. 1 Department of Otolaryngology, Head and Neck Surgery, PLA General Hospital, Beijing, China
  2. 2 Department of Otolaryngology, The General Hospital of the PLA Rocket Force, Beijing, China
  3. 3 BGI-Shenzhen, Beishan Industrial Zone, Shenzhen, China
  4. 4 China National GeneBank, BGI-Shenzhen, Shenzhen, China
  5. 5 Department of Audiology and Balance Science, Xuzhou Medical University, Xuzhou, China
  6. 6 Department of Otolaryngology, Xi’an Medical College, Xi’an, China
  7. 7 Department of Otolaryngology, Head and Neck Surgery, Shanxi Medical University, Taiyuan, China
  8. 8 Department of Otolaryngology, Fujian Medical University ShengLi Clinical College, Fujian Provincial Hospital, Fuzhou, China
  1. Correspondence to Dr Pu Dai, Department of Otolaryngology, Head and Neck Surgery, PLA General Hospital, Beijing, 100853, China; daipu301{at}vip.sina.com

Abstract

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.

  • ADNSHL
  • deafness gene
  • IFNLR1
  • JAK/STAT pathway

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/jmedgenet-2017-104954

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    Footnotes

    • XG, Y-YY and Q-FL contributed equally.

    • Contributors XG, Y-YY, Q-FL and PD conceived of the study and participated in its design and drafted the manuscript. J-CX, L-PG, S-SH, H-KL and G-JW participated in the data interpretation and analysis. Y-HQ, W-QW, S-WQ, FX, YS, M-YH, YJ, DB and D-YK participated in the experiment in vivo and in vitro. All authors read and approved the final manuscript.

    • Funding This work was supported by National Natural Science Foundation of China (81730029, 81371096) and National key research and development project (2016YFC1000700, 2016YFC1000704) to PD; grants from National Natural Science Foundation of China (81570929) to XG; grants from National key research and development project (2016YFC1000706) and National Natural Science Foundation of China (81371098) to Y-YY; grants from National Natural Science Foundation of China (81360159) and National Basic Research Program of China (2014CB541706) to G-JW; grants from Military Health Care Special Project (15BJZ23) to J-CX; grants from National Natural Science Foundation of China (81200751) to S-SH; grants from National Natural Science Foundation of China (81400471) to YS; grants from Natural Science Foundation of Hainan Province (817345) to M-YH.

    • Disclaimer The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Chinese People’s Liberation Army General Hospital Research Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.