Novel loss-of-function mutations in COCH cause autosomal recessive nonsyndromic hearing loss
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ORIGINAL INVESTIGATION
Novel loss‑of‑function mutations in COCH cause autosomal recessive nonsyndromic hearing loss Kevin T. Booth1,2 · Amama Ghaffar3 · Muhammad Rashid4 · Luke T. Hovey1 · Mureed Hussain3 · Kathy Frees1 · Erika M. Renkes1 · Carla J. Nishimura1 · Mohsin Shahzad5 · Richard J. Smith1 · Zubair Ahmed3 · Hela Azaiez1 · Saima Riazuddin3 Received: 4 May 2020 / Accepted: 12 June 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in COCH, 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) in COCH as 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 in COCH in 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.
Introduction The harmonious interplay between many proteins is required for normal auditory function. Mutations in genes encoding these proteins give rise to hearing loss. Each of these genes Kevin T. Booth and Amama Ghaffar are co-first authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-020-02197-5) contains supplementary material, which is available to authorized users. * Hela Azaiez hela‑[email protected] Richard J. Smith richard‑[email protected] Saima Riazuddin [email protected] 1
Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA
Department of Neurobiology, Harvard Medical School, Boston, MA, USA
2
has a distinct genomic and mutational signature (Azaiez et al. 2018). For some genes, variant location and variant type correlate with specific phenotypic outcomes as a consequence of the pathogenic mechanism at play; such is the case with the COCH gene (Bae et al. 2014; Janssensdevarebeke et al. 2018; Mehregan et al. 2019). Cochlin, the protein product of the COCH gene, is a large secreted
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