Pathological Features in the LmnaDhe/+ Mutant Mouse Provide a Novel Model of Human Otitis Media and Laminopathies

Genetic predisposition is recognized as an important pathogenetic factor in otitis media (OM) and associated diseases. Mutant Lmna mice heterozygous for the disheveled hair and ears allele (LmnaDhe/+) exhibit early-onset, profound hearing deficits and other pathological features mimicking human laminopathy associated with the LMNA mutation. We assessed the effects of the LmnaDhe/+ mutation on development of OM and pathological abnormalities characteristic of laminopathy. Malformation and abnormal positioning of the eustachian tube, accompanied by OM, were observed in all of the LmnaDhe/+ mice (100% penetrance) as early as postnatal day P12. Scanning electronic microscopy revealed ultrastructural damage to the cilia in middle ears that exhibited OM. Hearing assessment revealed significant hearing loss, paralleling that in human OM. Expression of NF-κB, TNF-α, and TGF-β, which correlated with inflammation and/or bony development, was up-regulated in the ears or in the peritoneal macrophages of LmnaDhe/+ mice. Rugous, disintegrative, and enlarged nuclear morphology of peritoneal macrophages and hyperphosphatemia were found in LmnaDhe/+ mutant mice. Taken together, these features resemble the pathology of human laminopathies, possibly revealing some profound pathology, beyond OM, associated with the mutation. The LmnaDhe/+ mutant mouse provides a novel model of human OM and laminopathy