ENU derived mouse line AEA001: A model for osteoporosis carrying a mutation in Ednra
ABSTRACT: Transcriptome analysis of white adipose tissue and bone (femur of the hind limbs) of the AEA001 mutant mouse. ENU generated mouse lines for osteoporosis. The mutation in the Ednra gene causes big ears and a flat short head. Due to a decreased body mass and a trend towards decreased glucose level white adipose tissue was analysed. Total RNA obtained from 4 male mutant mice was compared to 4 controls.
Project description:Human velocardiofacial syndrom/DiGeorg (VCFS/DGS) syndrom is a complex developmental disease with various expression of a large number of phenotypes. Craniofacial, cardiac, behavioural and endocrinological phenotypes are cardinal symptoms liked to the 22Q11.2 deletion occuring in 1/4.000 births. Several genes located within the 1.5 to 3 Mb deletion resemble a number of phenotypes demonstrated in mouse models for these genes including the endothelin receptor A (Ednra) gene. This is the first report on gene dosage effects observed in a dominant mouse model carrying an EdnraY129F point-mutation. EdnraY129F/+ mice are viable despite a strong cardiac phenotype alike to Fallot's tetralogy concomitant with cardiofacial, otolaryngeal phenotypes and deafness. Total RNA obtained from 4 male heterzygote and 4 male wildtype mice
Project description:A new mouse mutant was identified at the Munich ENU mutagenesis project due to hyperactivity, head tossing, and circling behaviour. Neurological and gross morphological phenotyping of these mutant mice revealed impairment of the vestibular system. Using whole genome exome sequencing and a custom-made variant calling pipeline, we identified the causative mutation as an A->T substitution on the chromosome 2 at the position 128 in the exon 6 of jagged 1 (Jag1) gene. This introduces a premature termination codon at the position 883 of the cDNA. In humans, mutations in the JAG1 gene are associated with Alagille syndrome (ALGS1 ), a multisystem developmental disorder mainly affecting small bile ducts in the liver, but also heart, skeleton, and eyes, and occasionally also kidney or inner ears. Further examination of the Jag1K295*/+ mutant mouse line disclosed multiorgan deficiencies, such as cardiac liver congestion, bile duct hypoplasia, mild nephropathy, subvalvular hypertrophy of the right ventricle, and mild growth retardation. No skeletal abnormalities could be detected. In summary, we report a novel mouse model for Alagille syndrome, Jag1K295*/+, which resembles most of the features of the mild form of Alagille syndrome observed in patients. Total RNA obtained from liver of 4 male heterozygous Jag1K295*/+ and 4 male wildtype mice
Project description:Increased levels of blood plasma urea were used as phenotypic parameter for establishing novel mouse models for kidney diseases on the genetic background of C3H inbred mice in the phenotype-driven Munich ENU mouse mutagenesis project. The phenotypically mutant line HST014 was established and further analyzed. The causative mutation was detected in the gene Kctd1 which leads to the amino acid exchange Kctd1I27N thereby affecting the functional BTB domain of the protein. This line is the first mouse model harbouring a Kctd1 mutation. Kctd1I27N homozygous mutant mice die perinatally. Standardized, systemic phenotypic analysis of heterozygous mutants was carried out in the German Mouse Clinic. Systematic morphological investigation of the external physical appearance found no mutation-specific differences. Main phenotypic changes were kidney dysfunction, minor cardiovascular and neurological alterations as well as low plasma corticosterone levels. Genome-wide RNA expression analysis at the age of 4 months revealed few regulated genes in brain and heart, and over 100 significantly regulated genes in kidneys of heterozygous mutants. Total RNA obtained from 4 mutant and 5 wild type control mice
Project description:The generation of optimal immune response requires combined activation of both T- and B-cells. Here, we demonstrate that the cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel factor that governs activation of both T- and B-cells in vivo. Upon ovalbumin challenge, CIP2A-deficient (CIP2AHOZ) mice show impaired immune response. Furthermore, CIP2AHOZ mice had impaired clearance of Listeria Monocytogenesis (L.m.) infection, combined with decreased numbers of CD8+ T-cells and IFN-γ secretion. In an ovalbumin model of allergic asthma, CIP2AHOZ B-cells were impaired in IgE and IgG secretion, despite of normal Th2 differentiation and unaffected numbers of inflammatory cells or cytokines in bronchoalveolar lavage. Importantly, the cell-autonomous effect of CIP2A deficiency for both T- and B-cell activation was confirmed by in vitro assays. During the T-cell activation CIP2A, was shown to promote expression of ETS-1, whereas in B-cells CIP2A loss resulted in inhibition of MYC-mediated gene expression. Together these results identify CIP2A as a novel cell-autonomous regulator governing both T- and B-cell activation in vivo. They also identify CIP2AHOZ as a novel murine model for investigation of impaired immune response and allergic asthma. Total RNA obtained from 4 male mutant mice was compared to 4 wild type controls.
Project description:Analysis of rapamycin effects on white adipose tissue at gene expression level. The hypothesis tested in the present study was that rapamycin could modify immune cell composition and inflammatory state of the adipose tissue of obese mice. Total RNA prepared from the adipose tissue of obese mice treated with rapamycin or its excipient solution (referred as vehicle), compared to adipose tissue of lean mice.
Project description:Within a mutatgenesis screen, we identified the new recessive mouse mutant KTA48 with a kinky tail, white spots on coat and with small eyes. Aim of the actual study was the molecular characterization of the mutant and the functional consequences of the mutation. We mapped the mutation to mouse chromosome 12 within a critical interval of 2.4 Mb between the markers D12Mit171 and D12Mit270; sequence analysis of Pxdn revealed a T->A mutation at position 3816 (T3816A) resulting in a premature stop codon (Cys1272X) in teh perosidasin domain. Histological analysis revealed variable, but severe defects in teh eye including all major ocular tissues (cornea, lens and retina). These findings demonstrate severe clinical findings of a recessive mutation affecting peroxidasin. Total RNA obtained from homozygote embryos E12.5 and wildtype embryos E12.5, each sample include 4 eyes of two embryos
Project description:Analysis of changes on gene expression levels in brain and bone for the linkage to phenotypical alterations found in behavior, neurology, nociception, bone remodelling and development. Total RNA isolated from bone and brain of Ali35 mutant mice compared to wildtype controls
Project description:TDP-43-coding mutations are found among ALS patients. In oder to express human mutant TDP-43 protein in the mouse under the control of the endogenous Tardp promoter, we have generate a mouse line wit 300% elevated TDP-43 level. Total RNA obtained from 4-6 male mutant mice was compared to 4-6 wild type controls.
Project description:Members of the HMGN protein family bind to nucleosomes and affect chromatin structure and functions as transcription, replication and DNA repair as well as epigenetic modifications. Overexpression of Hmgn1 may be linked to the etiology of Down syndrome while underexpression may be linked to some leukemias. Hmgn3 is highly expressed in eye and in brain and might influence behavioral phenotype. For Hmgn5 effects on transcription levels e.g. in liver are suggested. Total RNA obtained from four homozygote mutant and wildtype male mice were compared.
Project description:The function of the SMC5-6 complex is less clear, but it has an important role in a variety of different DNA repair processes and in resolving recombination structures. Interestingly mutation at a highly conserved residue (Ser994) in the ATP hydrolysis motif in the SMC6 C-terminal domain, resulted in mice with a mild phenotype. Total RNA obtained from homozygote 4 male mutant mice was compared to 2-4 wild type or 2 heterozygote controls.