Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans

Conductive hearing loss occurs when sound waves are not relayed efficiently to the inner ear. Mutations of the NOGGIN (NOG) gene in humans are associated with several autosomal dominant disorders such as proxi-mal symphalangism and multiple synostoses. These syndromes are characterized by skeletal defects and synostoses, which include conductive hearing loss. Noggin is an antagonist of bone morphogenetic proteins (BMPs), and balanced levels of BMPs and Noggin are required for proper skeletal formation. Depending on the genetic background, some of the Nog1/2 mice display mild hearing loss, that is, conductive in nature. Since Noggin is a single exon gene, this data strongly suggest that the autosomal dominant disorders associ-ated with NOG mutations are due to haploinsufficiency of NOGGIN. The conductive hearing loss in Nog1/2 mice is caused by an ectopic bone bridge located between the stapes and the posterior wall of the tympanum, which affects the normal mobility of the ossicle. Our analyses suggest that the ectopic bone formation is caused by a failure of the stapes and styloid process to separate completely during development. This failure of bone separation in the Nog1/2 mice reveals another consequence of chondrocyte hyperplasia due to unopposed Bmp activities in these mutants such as Bmp4 and Bmp14 (Gdf5). More importantly, these results establish Nog1/2 mice as the first animal model for the study of conductive rather than neurosensory hearing loss that has direct relevance to human genetic disorders