Novel Loss-of-Function Mutations inCOCHCause Autosomal Recessive Nonsyndromic Deafness

Abstract

COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly deafness in mice and humans. Two forms of deafness are linked to mutations in COCH, the wellestablished 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 mini-gene 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.

On the pathophysiology of DFNA9: Effect of pathogenic variants in the COCH gene on inner ear functioning in human and transgenic mice

“…In contrast to DFNA9, DNFB110 is the autosomal recessive variant caused by inactivating variants. [19] Today, we know of six families that carry loss-of-function mutations in the COCH gene.…”

“…[20] An overview of the different loss-of-function mutations affecting the COCH gene is given in Table 1. [19,20,21] including vertigo spells, hearing loss, tinnitus or aural fullness, which may lead to a diagnostic delay. [22] Despite the fact that MD patients do not carry pathogenic variants in the COCH gene, it is observed that in the vestibular end organs from definite MD patients cochlin is upregulated when compared to normal human vestibular end organs.…”

“…In patients, there are a few loss-of-function mutations in the COCH gene leading to functional COCH knockouts, causing DFNB110. These patients suffer from congenital moderate sensorineural hearing loss [19,21]. In contrast to the human situation, the mouse knockout for the Coch gene only has elevated ABR thresholds at the age of 21 months at the highest frequency tested (41.2 kHz).…”