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The non-imprinted in Prader-Willi/Angelman syndrome (NIPA) proteins are highly conserved receptors or transporters. Translocation of NIPA genes were found in patients with Prader-Willi syndrome, and loss-of-function of the NIPA1 gene was identified in hereditary spastic paraplegia. The family of NIPA-like domain containing (NPAL) proteins is closely related to the NIPA proteins, but to date nothing is known about their function. Here, we could demonstrate that both human NPAL3 and mouse Npal3 are ubiquitously expressed and encode highly conserved proteins. To further elucidate the function of the Npal3 gene, knockout (Npal3–/–) mice were generated. Intensive phenotypic analyses revealed that disruption of the Npal3 gene results in a pleiotropic phenotype. The function of the nervous system was impaired in both mutant males and females which could be demonstrated in behavioral tests. In addition, in Npal3 mutants the number of NK cells was decreased and changes in IgM, IgG2, and IgA were observed, indicating that the immune system is also affected. Interestingly, increased IgE levels as well as impaired lung functions were observed in mutant males but not in mutant females. It should be noted that the human NPAL3 gene is located at 1p36.12→p35.1, and atopic diseases were previously linked to this genomic region. Thus, the Npal3–/– mice could serve as a valuable model system for studying atopic diseases. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Obesity is associated with increased risk for developing pancreatic cancer, and it is suggested that insulin resistance provides the missing link. Here we demonstrate that under the context of genetic susceptibility, a high fat diet (HFD) predisposes mice with oncogenic K-ras activation to accelerated pancreatic intraepithelial neoplasm (PanIN) development. Tumor promotion is closely associated with increased inflammation and abrogation of TNFR1 signaling significantly blocks this process underlining a central role for TNFα in obesity-mediated enhancement of PanIN lesions, Interestingly, however, despite increased TNFα levels, mice remain insulin sensitive. We show that, while aggravating tumor promotion, a HFD exerts dramatic changes in energy metabolism through enhancement of pancreatic exocrine insufficiency, metabolic rates, and expression of genes involved in mitochondrial fatty acid (FA) β-oxidation that collectively contribute to improved glucose tolerance in these mice. While on one hand these findings provide significant evidence that obesity is linked to tumor promotion in the pancreas, on the other it suggests alterations in inflammatory responses and bioenergetic pathways as the potential underlying cause. [ABSTRACT FROM AUTHOR]

Candidate genes for amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are located on 4q21 in humans. We tested our hypothesis that mutations in the portion of mouse chromosome 5 corresponding to human chromosome 4q21 would cause enamel and dentin abnormalities. Male C3H mice were injected with ethylnitrosourea (ENU). Within a dominant ENU mutagenesis screen, a mouse mutant was isolated with an abnormal tooth enamel (ATE) phenotype. The structure and ultrastructure of teeth were studied. The mutation was located on mouse chromosome 5 in an interval of 9 cM between markers D5Mit18 and D5Mit10. Homozygotic mutants showed total enamel aplasia with exposed dentinal tubules, while heterozygotic mutants showed a significant reduction in enamel width. Dentin of mutant mice showed a reduced content of mature collagen cross-links. We were able to demonstrate that a mutation on chromosome 5 corresponding to human chromosome 4q21 can cause amelogenesis imperfecta and changes in dentin composition. [ABSTRACT FROM AUTHOR]

Purpose The mouse mutant KTA48 was identified within the recessive Munich ENU Project among offspring of treated C3HeB/FeJ mice. It is characterized by a kinky tail, white belly spot and small dull eyes. Methods Linkage analysis was performed using SNP‐based technology and microsatellite markers. Sequence analysis, histology and in‐situ hybridization were performed according to standard techniques. Results The genome‐wide linkage analysis mapped the KTA48 mutation on chromosome 12; positional candidate gene analysis detected a mutation in the Pxdn gene (encoding peroxidasin) co‐segregating with the mutation. The Pxdn‐mRNA of the KTA48 mutants contains a T‐>A mutation at pos. 3816 (T3816A) creating a new Alw26I restriction site; the mutation converts the Cys at codon 1272 into a stop codon (Cys1272X). The mutation co‐segregates with the phenotype in the breeding colony; it is not present in several wild‐type strains. The lens phenotype is slightly variable. During an early stage of eye development (E12.5), Pxdn is expressed in the posterior part of the lens and in the central part of the retina without obvious changes. At the end of embryonic development (E17.5), we observed small lenses outside the optical axis and rupture of the lens capsule. Later, microphagia is accompanied by deformed cornea and multilayered retina. At P21, the small lens is attached to the cornea, and in some cases, the eye is completely disorganized.. Conclusion The recessive mouse mutation KTA48 is caused by a premature stop codon of the Pxdn gene. The function of Peroxidasin is still unknown; there is no mutation known neither in humans nor in mice. [ABSTRACT FROM AUTHOR]