Cingulin regulates hair cell cuticular plate morphology and is required for hearing in human and mouse

Cingulin (CGN) is a cytoskeleton-associated protein localized at the apical junctions of epithelial cells. CGN interacts with major cytoskeletal filaments and regulates RhoA activity. However, physiological roles of CGN in development and human diseases are currently unknown. Here, we report a multi-generation family presenting with autosomal dominant non-syndromic hearing loss (ADNSHL) that co-segregates with a CGN heterozygous truncating variant, c.3330delG (p.Leu1110Leufs*17). CGN is normally expressed at the apical cell junctions of the organ of Corti, with enriched localization at hair cell cuticular plates and circumferential belts. In mice, the putative disease-causing mutation results in reduced expression and abnormal subcellular localization of the CGN protein, abolishes its actin polymerization activity, and impairs the normal morphology of hair cell cuticular plates and hair bundles. Hair cell-specific Cgn knockout leads to high-frequency hearing loss. Importantly, Cgn mutation knockin mice display noise-sensitive, progressive hearing loss and outer hair cell degeneration. In summary, we identify CGN c.3330delG as a pathogenic variant for ADNSHL and reveal essential roles of CGN in the maintenance of cochlear hair cell structures and auditory function. imageThe tight junction-related protein Cingulin (CGN) is a novel deafness gene required for maintenance of cochlear hair cell cuticular plates and hair bundles. A frameshift mutation in CGN results in progressive hearing loss in human and mouse model.A frameshift mutation in CGN co-segregates with autosomal dominant non-syndromic hearing loss in a Chinese family.CGN is enriched at the apical cuticular plates and circumferential belts of cochlear hair cells.CGN mutation impairs its expression and localization, alters the morphology of hair cell cuticular plates and hair bundles.CGN mutation results in progressive and noise-sensitive hearing loss in the disease mouse model. The tight junction-related protein Cingulin (CGN) is a novel deafness gene required for maintenance of cochlear hair cell cuticular plates and hair bundles. A frameshift mutation in CGN results in progressive hearing loss in human and mouse model.image

Automated summary

CGN is a cytoskeleton-associated protein that regulates RhoA activity and is found at the apical junctions of epithelial cells. A truncating variant of CGN has been identified as a pathogenic variant for autosomal dominant non-syndromic hearing loss, leading to reduced expression and abnormal localization of CGN, as well as impaired morphology of cochlear hair cell structures and auditory function.