Coch-KO Mouse

Check the content of the review COCH, also known as coagulation factor C homolog, encodes cochlin, a protein abundantly expressed in the spiral ligament and spiral limbus of the inner ear [3]. While its exact function remains unclear, it is associated with the development of sensorineural hearing loss and vestibular dysfunction [3]. Mouse models have been developed to better understand the pathology underlying DFNA9, a dominant hereditary non-syndromic form of progressive sensorineural hearing loss often associated with vestibular dysfunction caused by pathogenic variants in the COCH gene [3].

Pathogenic missense variants in COCH are linked to DFNA9. Studies have found significant differences in the ages of onset and progression of audiovestibular phenotypes between subjects with pathogenic variants affecting different domains of cochlin [1]. For example, variants affecting the LCCL domain generally lead to more hearing loss progression compared to those affecting other domains [1]. Functional studies on COCH-related hearing loss in both East Asian and European-descent families showed that deafness-associated variants in non-LCCL domains of cochlin caused more severe hearing loss earlier in life [2]. A systematic review of the Pro51Ser COCH mutation carriers found that the sensorineural hearing loss starts at around 32.8 years old, with an annual threshold deterioration of 3 dB HL per year, and profound loss at 76 years on average, while vestibular dysfunction onset was around 34 years old with higher deterioration rates [4]. A novel COCH p.D544Vfs*3 variant was found to increase the formation of multimeric cochlin, enriching the spectrum of DFNA9-linked pathological COCH variants [5]. A new COCH mutation (c.1312C > T p.(Arg438Cys)) affecting the vWFA2 domain led to a relatively mild audiovestibular phenotype compared to other COCH mutations [6].

In conclusion, COCH is crucial in inner-ear-related functions, and its dysfunction is closely associated with DFNA9. Studies using mouse models and human genetic analyses have revealed the genotype-phenotype correlations of COCH variants, which are valuable for understanding the mechanisms of sensorineural hearing loss and vestibular dysfunction, and may contribute to the development of mutation-specific therapeutic interventions [1,3].