Genetics of Otosclerosis

Unlike all other bones in the human skeleton, the otic capsule undergoes very little remodeling after development, possibly due to local inner ear factors. Otosclerosis is a process of pathologic increased bone turnover in the otic capsule, which in most cases leads to stapes fixation, resulting in a conductive hearing loss. Although environmental factors such as estrogens, fluoride, and viral infection have been implicated, it is clear that genetic factors play a significant role in the manifestation of otosclerosis. From a genetic viewpoint, otosclerosis is considered to be a complex disease with rare autosomal dominant forms caused by a single gene. Already, 7 monogenic loci have been published, but none of the genes involved have been identified. For the complex form of otosclerosis, caused by an interaction between genetic and environmental factors, the first susceptibility genes were identified by case-control association studies. All 3 replicated genes, TGFB1, BMP2, and BMP4, are a part of the transforming growth factor-beta1 pathway. Data from both genetic association studies and gene expression analysis of otosclerotic bone showed that the TGF-beta1 pathway is most likely an important factor in the pathogenesis of otosclerosis.