Journal article
Novel loss-of-function mutations inCOCHcause autosomal recessive nonsyndromic hearing loss
Human genetics, Vol.139(12), pp.1565-1574
12/01/2020
DOI: 10.1007/s00439-020-02197-5
PMCID: PMC7572817
PMID: 32562050
Abstract
COCHis the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations inCOCHunderly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations inCOCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing, and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense, and one inframe deletion) inCOCHas the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used minigene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations inCOCHin autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing.
Details
- Title: Subtitle
- Novel loss-of-function mutations inCOCHcause autosomal recessive nonsyndromic hearing loss
- Creators
- Kevin T Booth - Harvard UniversityAmama Ghaffar - University of Maryland, BaltimoreMuhammad Rashid - University of Health Sciences LahoreLuke T Hovey - University of IowaMureed Hussain - University of Maryland, BaltimoreKathy Frees - University of IowaErika M Renkes - University of IowaCarla J Nishimura - University of IowaMohsin Shahzad - Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.Richard J Smith - University of IowaZubair Ahmed - University of Maryland, BaltimoreHela Azaiez - University of IowaSaima Riazuddin - University of Maryland, Baltimore
- Resource Type
- Journal article
- Publication Details
- Human genetics, Vol.139(12), pp.1565-1574
- DOI
- 10.1007/s00439-020-02197-5
- PMID
- 32562050
- PMCID
- PMC7572817
- NLM abbreviation
- Hum Genet
- ISSN
- 0340-6717
- eISSN
- 1432-1203
- Publisher
- SPRINGER
- Number of pages
- 10
- Grant note
- R01 DC002842; R01 DC012049; R01 DC017955; R56DC011803 / NIDCD
- Language
- English
- Date published
- 12/01/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984256841302771
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