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Mouse Screen Reveals Multiple New Genes Underlying Mouse and Human Hearing Loss King’s Research Portal DOI: 10.1371/journal.pbio.3000194 Document Version Publisher's PDF, also known as Version of record Link to publication record in King's Research Portal Citation for published version (APA): Ingham, N. J., Pearson, S. A., Vancollie, V. E., Lewis, M. A., Chen, J., Buniello, A., Martelletti, E., & Steel, K. (2019). Mouse screen reveals multiple new genes underlying mouse and human hearing loss. PLoS biology, 17(4), [e3000194]. https://doi.org/10.1371/journal.pbio.3000194 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. 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Download date: 04. Oct. 2021 RESEARCH ARTICLE Mouse screen reveals multiple new genes underlying mouse and human hearing loss 1,2 1 1 2 Neil J. InghamID , Selina A. Pearson , Valerie E. VancollieID , Victoria RookID , Morag 1,2 1,2 1,2 2 2 A. LewisID , Jing Chen , Annalisa BunielloID , Elisa MartellettiID , Lorenzo Preite , Chi 2 2 3 4 1 Chung LamID , Felix D. WeissID , ZoÈ e Powis , Pim Suwannarat , Christopher J. LelliottID , 5 1 1,2 Sally J. Dawson , Jacqueline K. White , Karen P. SteelID * 1 Wellcome Trust Sanger Institute, Hinxton, United Kingdom, 2 Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom, 3 Department of Emerging Genetics Medicine, Ambry Genetics, Aliso Viejo, California, United States of a1111111111 America, 4 Mid-Atlantic Permanente Medical Group, Rockville, Maryland, United States of America, 5 UCL a1111111111 Ear Institute, University College London, London, United Kingdom a1111111111 a1111111111 * [email protected] a1111111111 Abstract Adult-onset hearing loss is very common, but we know little about the underlying molecular OPEN ACCESS pathogenesis impeding the development of therapies. We took a genetic approach to iden- Citation: Ingham NJ, Pearson SA, Vancollie VE, tify new molecules involved in hearing loss by screening a large cohort of newly generated Rook V, Lewis MA, Chen J, et al. (2019) Mouse mouse mutants using a sensitive electrophysiological test, the auditory brainstem response screen reveals multiple new genes underlying mouse and human hearing loss. PLoS Biol 17(4): (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associ- e3000194. https://doi.org/10.1371/journal. ated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, pbio.3000194 suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was Academic Editor: Thomas C. Freeman, University found, and some mutant lines showed normal development followed by deterioration of of Edinburgh, UNITED KINGDOM responses, revealing new molecular pathways involved in progressive hearing loss. Several Received: November 6, 2018 of the genes were associated with the range of hearing thresholds in the human population Accepted: March 7, 2019 and one, SPNS2, was involved in childhood deafness. The new pathways required for main- tenance of hearing discovered by this screen present new therapeutic opportunities. Published: April 11, 2019 Copyright: © 2019 Ingham et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and Author summary reproduction in any medium, provided the original author and source are credited. Progressive hearing loss with age is extremely common in the population, leading to diffi- culties in understanding speech, increased social isolation, and associated depression. We Data Availability Statement: All mutant mice know it has a significant heritability, but so far we know very little about the molecular reported here are available via public mouse repositories for further investigation. All plotted pathways leading to hearing loss, hampering the development of treatments. Here, we data points are presented in the data files in the describe a large-scale screen of 1,211 new targeted mouse mutant lines, resulting in the Supporting Information. The unprocessed ABR identification of 38 genes underlying hearing loss that were not previously suspected of data are available at Dryad (http://dx.doi.org/10. involvement in hearing. Some of these genes reveal molecular pathways that may be useful 5061/dryad.cv803rv). targets for drug development. Our further analysis of the genes identified and the varied Funding: This work was supported by The pathological mechanisms within the ear resulting from the mutations suggests that hearing Wellcome Trust (KPS, 098051; 100699; 089622), loss is an extremely heterogeneous disorder and may have as many as 1,000 genes involved. the Medical Research Council (KPS, MC_qA137918; G0300212), European PLOS Biology | https://doi.org/10.1371/journal.pbio.3000194 April 11, 2019 1 / 30 Mouse screen reveals multiple new genes underlying hearing loss Commission (KPS, EUMODIC contract LSHG-CT- 2006-037188), Action on Hearing Loss (KPS), the Introduction Haigh Fellowship in age related deafness (SJD), Hearing loss is a very common disorder with a significant social impact, including delayed and Deafness Research UK (SJD). This work made speech and language development, reduced academic achievement, increased social isolation, use of data and samples generated by the 1958 Birth Cohort (http://www2.le.ac.uk/projects/ and risk of depression, and has recently been reported to be a major risk factor for dementia birthcohort, http://www.bristol.ac.uk/alspac/, http:// [1], adding new impetus to the need to develop therapies. Approximately 1 in 850 children are www.cls.ioe.ac.uk/ncds, http://www.esds.ac.uk/ born with permanent hearing impairment in the United Kingdom [2], and the number of peo- findingData/ncds.asp) under grant G0000934 from ple affected by adult-onset hearing loss increases with each decade of life, with 60% of people the Medical Research Council and grant 068545/Z/ in their 70s having a hearing loss of 25 dB or worse [3]. Environmental factors including noise 02 from the Wellcome Trust. Genotyping was undertaken as part of the Wellcome Trust Case- or drug exposure play an important role in its etiology, but there is also a strong genetic contri- Control Consortium (WTCCC) under Wellcome bution. Over 360 genes are known to be involved in human or mouse deafness, but ascertain- Trust award 076113, and a full list of the ment bias has led to many of these having early developmental effects, and little is known investigators who contributed to the generation of about the genetic contribution to adult-onset hearing loss. We set out to identify further genes the data is available at www.wtccc.org.uk. The underlying deafness, including those with mild effects, using a physiological screen based on funders had no role in study design, data collection the auditory brainstem response (ABR) in a large cohort of newly generated targeted mouse and analysis, decision to publish, or preparation of the manuscript. mutants. In this report, we review the findings from this screen and present the new data; both mice and ABR waveform data are available for further analysis. From the unbiased sample of Competing interests: I have read the journal's 1,211 genes tested, we found 38 unexpected genes to be involved in hearing impairment. This policy and the authors of this manuscript have the following competing interests: ZP is employed by indicates that around 600 additional genes remain to be found (see later), making deafness an Ambry Genetics, and exome sequencing is among extremely heterogeneous condition, with around 1,000 genes that may contribute. The the commercially available tests. The other authors observed impairments ranged from mild to profound, including several with progressive hear- have declared that no competing interests exist. ing loss, and with a wide range of underlying pathological mechanisms. The 38 genes represent Abbreviations: ABR, auditory brainstem response; a range of functions from transcription factors and a microRNA to enzymes involved in lipid DPOAE, distortion product otoacoustic emission; metabolism. Eleven were found to be significantly associated with auditory function in the EP, endocochlear potential; ER, endoplasmic human population, and one gene, SPNS2, was associated with childhood deafness, emphasis-
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