Tmco1-Deficient Mice Exhibit a High Incidence of Otitis Media Associated with Impaired Bone Homeostasis in the Middle Ear

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome (CFSMR1; Online Inheritance in Man number 213980) is characterized by craniofacial dysmorphism, skeletal anomalies, and mental retardation. However, reports of hearing issues have been limited. To investigate hearing-related aspects of CFSMR1, Tmco1 knockout mice (Tmco1^−/−) exhibiting similar symptoms to human patients were used in this study. Otitis media (OM) was discovered in approximately 80% of Tmco1^−/− mice, which led to moderate conductive hearing loss at 3 months old and further progressed to deafness 2 months later. Pathology studies of Tmco1^−/− mice revealed a thickened middle ear (ME) epithelium and pronounced inflammatory infiltrates in the ME cavity and Eustachian tube of Tmco1^−/− OM mice. Micro–computed tomography scan of 5-month–old Tmco1^−/− OM mice showed significantly reduced ME volume and ME malformation. Tartrate-resistant acid phosphatase and Runt-related transcription factor 2, receptor activator of NF-κB ligand expression in ME revealed increased osteoclast activity and significantly decreased bone formation, suggesting potential causes of ME malformation. This study represents the first report of the audiological characteristics and the elucidation of potential mechanisms in Tmco1^−/− mice. It enriches our understanding of the phenotypes associated with CFSMR1 in the field of otology and provides a promising model for chronic OM with conductive hearing loss.