Rare variants in BMP2 and BMP4 found in otosclerosis patients reduce Smad signaling.

Hypothesis: Genetic variation in BMP2 and BMP4 found in otosclerosis patients result in altered Smad signaling.

Background: Otosclerosis is a common form of adult-onset conductive hearing loss resulting from abnormal bone remodeling of the bony labyrinth that surrounds the inner ear. Both genetic and environmental factors are implicated in the disease, yet very little is known about its pathogenesis. The evidence for a genetic component has been established through family-based linkage and population-based association studies. Previously, members of the TGF-β superfamily of genes have been associated with otosclerosis.

Methods: Sequencing of BMP2 and BMP4 coding regions was performed to identify common and rare variation in German otosclerosis patients compared with controls. Functional analyses of rare variation in the patient cohort were conducted by exposing an osteosarcoma cell line to conditioned media containing either wild type or variant forms of BMP2 or BMP4 and analyzing Smad1/5/8 phosphorylation.

Results: Although no significant association with common variation in these 2 genes was detected, there were 8 singleton variants identified in the German population. Of the 4 coding variants found solely in otosclerosis patients, two--BMP4(N150K) and BMP2(K357-R396del)--were found to decrease Smad1/5/8 signaling.

Conclusion: Rare variants in BMP2 and BMP4 are not a major genetic component in the otosclerosis population. However, those with functional affect showed decreased Smad signaling. Further analysis of Smad signaling molecules should be performed to determine if these pathways in combination are a major contributor to otosclerosis, which could lead to additional treatment options for otosclerosis patients.