title: Pathological features in the LmnaDhe/+ mutant mouse provide a novel model of human otitis media and laminopathies.
abstract: 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 (Lmna(Dhe/+)) exhibit early-onset, profound hearing deficits and other pathological features mimicking human laminopathy associated with the LMNA mutation. We assessed the effects of the Lmna(Dhe/+) 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 Lmna(Dhe/+) 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 Lmna(Dhe/+) mice. Rugous, disintegrative, and enlarged nuclear morphology of peritoneal macrophages and hyperphosphatemia were found in Lmna(Dhe/+) mutant mice. Taken together, these features resemble the pathology of human laminopathies, possibly revealing some profound pathology, beyond OM, associated with the mutation. The Lmna(Dhe/+) mutant mouse provides a novel model of human OM and laminopathy.
authors: Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Yan
authors: Y
authors: Zhang
authors: Heping
authors: H
authors: Yu
authors: Min
authors: M
authors: Xu
authors: Fengchan
authors: F
authors: Han
authors: Cong
authors: C
authors: Tian
authors: Suejin
authors: S
authors: Kim
authors: Elisha
authors: E
authors: Fredman
authors: Jin
authors: J
authors: Zhang
authors: Cindy
authors: C
authors: Benedict-Alderfer
authors: Qing Yin
authors: QY
authors: Zheng
mesh_terms: D000158:Acoustic Impedance Tests; D000818:Animals; D002118:Calcium / Q000097:blood; D002452:Cell Count; D002465:Cell Movement; D002923:Cilia / Q000473:pathology / Q000648:ultrastructure; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004432:Ear, Middle / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005064:Eustachian Tube / Q000002:abnormalities / Q000473:pathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007477:Ions / Q000097:blood; D034904:Lamin Type A / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D010033:Otitis Media / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D017084:Otoacoustic Emissions, Spontaneous / Q000502:physiology; D010758:Phosphorus / Q000097:blood; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007477:Ions; D034904:Lamin Type A; C576142:Lmna protein, mouse; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D010758:Phosphorus; D002118:Calcium