No abstract

The kidneys from six immunodeficient mice examined by Cerberus Sciences and the Animal Resources Centre, displayed karyomegaly with pale eosinophilic, intranuclear inclusions upon histopathological examination. Electron microscopy performed on kidney tissue from 5/6 mice demonstrated margination of the chromatin in large nuclei. Laboratory tests were used to detect nucleic acid of papillomaviruses, polyomaviruses, circoviruses and anelloviruses (4/6 mice), a specific PCR was used to detect murine polyomavirus (1/6), and a panel of serological tests was used to detect seroconversion to major murine pathogens (1/6). All molecular and serological tests were negative. Immunohistochemistry using polyclonal anti-bovine papillomavirus type 1 (BPV-1) L1 antibody, Camvir monoclonal anti-papillomavirus antibody (directed against the seven amino acids GFGAMDF found in human papillomavirus (HPV) 16 L1 protein), a commercially available mixture of two monoclonal antibodies, anti-BPV-1 L1/1H8 + Camvir antibodies, and a monoclonal anti-Hsc70 antibody revealed specific, positive staining of murine renal tubular epithelial intranuclear inclusions in 6/6 mice using the anti-BPV-1 L1 containing antibodies only. Methyl pyronin green, PAS and Feulgen histochemical reactions revealed that the intranuclear inclusions did not consist of RNA, DNA or carbohydrate. An immunohistochemical method now exists that can be used to confirm and evaluate suspected cases of murine inclusion body nephropathy.

seen does not explain the significant phenotypic heterogeneity observed in NM patients or mouse models, suggesting that additional factors determine disease phenotype. Proteomic assessments of skeletal muscles from the Acta1 H40Y, Acta1 D286G, and Neb cKO mouse models of NM identified cellular pathways affected in all mouse models. Interestingly, mitochondrial dysfunction was present in all models, yet different mitochondria-associated proteins were affected. These results suggested that mitochondrial function was differentially impaired in different NM models. Biochemical assays including respirometry, complex activity function of each element of the electron transport chain, glutathione, and citrate synthase were performed to identify specific dysfunctions. Respirometry revealed mitochondrial impairment relative to wildtype counterparts in the Acta1 H40Y and Neb cKO mouse models but not the Acta1 D286G mouse model. Citrate synthase and glutathione show all normal levels in mutant animals relative to their controls, suggesting that the dysfunction lies in the respiratory chain. Electron transport chain analysis is currently ongoing. These studies form a foundation for future work on the impact of mitochondrial dysfunction in NM and its role in phenotype variability in NM, with the ultimate goal of guiding the development of treatment strategies.