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

DeaFNess Autosomal Dominant 9 (DFNA9) is a dominant hereditary non-syndromic form of progressive sensorineural hearing loss often associated with vestibular dysfunction. DFNA9 is caused by pathogenic variants in the COCH gene. This gene encodes for cochlin, a protein that is abundantly expressed in the spiral ligament and spiral limbus of the inner ear but the function of cochlin is still not fully understood. There are 22 known pathogenic variants located in different domains of the COCH gene that can cause DFNA9, all expressing slightly different phenotypes. It is believed that COCH mutations affect the intracellular trafficking of cochlin which could explain the characteristic pathology seen in temporal bones of DFNA9 patients. This pathology involves a widespread accumulation of acellular eosinophilic deposits throughout the labyrinth. To gain a better understanding of the pathology underlying DFNA9, different mouse models were developed. The objective of this review is to describe the different pathogenic variants in the COCH gene and their effect on intracellular trafficking, associated phenotypes and histopathological findings in both patients and mouse models.