Standardized, systemic phenotypic analysis of Umod(C93F) and Umod(A227T) mutant mice.
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ABSTRACT:
SUBMITTER: Kemter E
PROVIDER: S-EPMC3813435 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: Type I Bartter syndrome is a recessive human nephropathy caused by loss-of-function mutations in the SLC12A1 gene coding for the Na+-K+-2Cl- cotransporter NKCC2. We recently established the mutant mouse line Slc12a1I299F exhibiting kidney defects highly similar to the late-onset manifestation of this hereditary human disease. Besides the kidney defects, low blood pressure and osteopenia were revealed in the homozygous mutant mice which were also described in humans. Beside its strong expression in the kidney, NKCC2 has been also shown to be expressed in other tissues in rodents i.e. the gastrointestinal tract, pancreatic beta cells, and specific compartments of the ear, nasal tissue and eye. RESULTS: To examine if, besides kidney defects, further organ systems and/or metabolic pathways are affected by the Slc12a1I299F mutation as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the mutant mouse line Slc12a1I299F in the German Mouse Clinic. Slc12a1I299F homozygous mutant mice and Slc12a1I299F heterozygous mutant littermates as controls were tested at the age of 4-6 months. Beside the already published changes in blood pressure and bone metabolism, a significantly lower body weight and fat content were found as new phenotypes for Slc12a1I299F homozygous mutant mice. Small additional effects included a mild erythropenic anemia in homozygous mutant males as well as a slight hyperalgesia in homozygous mutant females. For other functions, such as immunology, lung function and neurology, no distinct alterations were observed. CONCLUSIONS: In this systemic analysis no clear primary effects of the Slc12a1I299F mutation appeared for the organs other than the kidneys where Slc12a1 expression has been described. On the other hand, long-term effects additional and/or secondary to the kidney lesions might also appear in humans harboring SLC12A1 mutations.
| S-EPMC4237776 | biostudies-literature
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 recessive mutant line HST011 was established and further analyzed. The causative mutation was detected in the POU domain, class 3 transcription factor 3 (Pou3f3) gene, which leads to the amino acid exchange Pou3f3L423P thereby affecting the conserved homeobox domain of the protein. Pou3f3 homozygous knockout mice are published and show perinatal death. Line Pou3f3L423P is a viable mouse model harboring a homozygous Pou3f3 mutation. Standardized, systemic phenotypic analysis of homozygous mutants was carried out in the German Mouse Clinic. Main phenotypic changes were low body weight and a state of low energy stores, kidney dysfunction and secondary effects thereof including low bone mineralization, multiple behavioral and neurological defects including locomotor, vestibular, auditory and nociceptive impairments, as well as multiple subtle changes in immunological parameters. Genome-wide transcriptome profiling analysis of kidney and brain of Pou3f3L423P homozygous mutants identified significantly regulated genes as compared to wild-type controls.
| S-EPMC4803225 | biostudies-literature
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
2014-05-02 | E-GEOD-47005 | biostudies-arrayexpress
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.
2014-05-02 | GSE47005 | GEO
Project description:BackgroundIncreased 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 dominant mutant line HST014 was established and further analyzed.MethodsAnalysis of the causative mutation as well as the standardized, systemic phenotypic analysis of the mutant line was carried out.ResultsThe causative mutation was detected in the potassium channel tetramerization domain containing 1 (Kctd1) gene which leads to the amino acid exchange Kctd1 I27N thereby affecting the functional BTB domain of the protein. This line is the first mouse model harboring a Kctd1 mutation. Kctd1 I27N homozygous mutant mice die perinatally. Standardized, systemic phenotypic analysis of Kctd1 I27N heterozygous mutants was carried out in the German Mouse Clinic (GMC). Systematic morphological investigation of the external physical appearance did not detect the specific alterations that are described in KCTD1 mutant human patients affected by the scalp-ear-nipple (SEN) syndrome. The main pathological phenotype of the Kctd1 I27N heterozygous mutant mice consists of kidney dysfunction and secondary effects thereof, without gross additional primary alterations in the other phenotypic parameters analyzed. Genome-wide transcriptome profiling analysis at the age of 4 months revealed about 100 differentially expressed genes (DEGs) in kidneys of Kctd1 I27N heterozygous mutants as compared to wild-type controls.ConclusionsIn summary, the main alteration of the Kctd1 I27N heterozygous mutants consists in kidney dysfunction. Additional analyses in 9-21 week-old heterozygous mutants revealed only few minor effects.
| S-EPMC5559776 | biostudies-literature
Project description:Mutations of the mouse Attractin (Atrn; formerly mahogany) gene were originally recognized because they suppress Agouti pigment type switching. More recently, effects independent of Agouti have been recognized: mice homozygous for the Atrn(mg-3J) allele are resistant to diet-induced obesity and also develop abnormal myelination and vacuolation in the central nervous system. To better understand the pathophysiology and relationship of these pleiotropic effects, we further characterized the molecular abnormalities responsible for two additional Atrn alleles, Atrn(mg) and Atrn(mg-L), and examined in parallel the phenotypes of homozygous and compound heterozygous animals. We find that the three alleles have similar effects on pigmentation and neurodegeneration, with a relative severity of Atrn(mg-3J) > Atrn(mg) > Atrn(mg-L), which also corresponds to the effects of the three alleles on levels of normal Atrn mRNA. Animals homozygous for Atrn(mg-3J) or Atrn(mg), but not Atrn(mg-L), show reduced body weight, reduced adiposity, and increased locomotor activity, all in the presence of normal food intake. These results confirm that the mechanism responsible for the neuropathological alteration is a loss--rather than gain--of function, indicate that abnormal body weight in Atrn mutant mice is caused by a central process leading to increased energy expenditure, and demonstrate that pigmentation is more sensitive to levels of Atrn mRNA than are nonpigmentary phenotypes.
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Project description:It has been proposed that a reduction in intracellular calcium causes an increase in intracellular cAMP and PKA activity through stimulation of calcium inhibitable adenylyl cyclase 6 and inhibition of phosphodiesterase 1 (PDE1), the main enzymes generating and degrading cAMP in the distal nephron and collecting duct, thus contributing to the development and progression of autosomal dominant polycystic kidney disease (ADPKD). In zebrafish pde1a depletion aggravates and overexpression ameliorates the cystic phenotype. To study the role of PDE1A in a mammalian system, we used a TALEN pair to Pde1a exon 7, targeting the histidine-aspartic acid dipeptide involved in ligating the active site Zn++ ion to generate two Pde1a null mouse lines. Pde1a mutants had a mild renal cystic disease and a urine concentrating defect (associated with upregulation of PDE4 activity and decreased protein kinase A dependent phosphorylation of aquaporin-2) on a wild-type genetic background and aggravated renal cystic disease on a Pkd2WS25/- background. Pde1a mutants additionally had lower aortic blood pressure and increased left ventricular (LV) ejection fraction, without a change in LV mass index, consistent with the high aortic and low cardiac expression of Pde1a in wild-type mice. These results support an important role of PDE1A in the renal pathogenesis of ADPKD and in the regulation of blood pressure.
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Project description:The lack of reproducibility with animal phenotyping experiments is a growing concern among the biomedical community. One contributing factor is the inadequate description of statistical analysis methods that prevents researchers from replicating results even when the original data are provided. Here we present PhenStat--a freely available R package that provides a variety of statistical methods for the identification of phenotypic associations. The methods have been developed for high throughput phenotyping pipelines implemented across various experimental designs with an emphasis on managing temporal variation. PhenStat is targeted to two user groups: small-scale users who wish to interact and test data from large resources and large-scale users who require an automated statistical analysis pipeline. The software provides guidance to the user for selecting appropriate analysis methods based on the dataset and is designed to allow for additions and modifications as needed. The package was tested on mouse and rat data and is used by the International Mouse Phenotyping Consortium (IMPC). By providing raw data and the version of PhenStat used, resources like the IMPC give users the ability to replicate and explore results within their own computing environment.
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Project description:Systemic lupus erythematosis is an autoimmune disease of unknown etiology. Lupus pathology is thought to reflect autoantibody-mediated damage due to a failure of B lymphocyte tolerance. Since excessive B cell-activating factor belonging to the TNF family (BAFF) expression correlates with human and murine lupus, and BAFF signals B cell survival through BAFF-R, it is believed that excessive BAFF-R signaling can subvert B cell tolerance and facilitate lupus development. Here we report the unexpected finding that BAFF-R-mutant A/WySnJ mice develop a lupus-like syndrome. These mice carry the B cell maturation defect-1 (Bcmd-1) mutant allele of the Baffr gene. Bcmd-1 causes premature B cell death and profound B cell deficiency. Despite having 90% fewer splenic B cells than normal mice, A/WySnJ mice had an 18-fold increased frequency of splenocytes secreting IgM antibodies to dsDNA, and increased amounts of circulating IgM and IgG to dsDNA by 9 months of age. By age 11 months, most A/WySnJ mice displayed renal pathology characteristic of lupus, including proteinuria as well as periodic acid-Schiff-positive deposits and glomerular capillary bed destruction. Importantly, we genetically linked this autoimmunity to Bcmd-1, since congenic AW.Baffr(+/+) mice carrying a wild-type allele developed none of these phenotypes. Our data provide the first evidence linking altered BAFF-R signaling to the development of B cell-mediated autoimmunity.
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Project description:Streptococcus mutans, a biofilm-forming Gram-positive bacterium that resides in the human oral cavity, is considered to be the primary aetiological agent of human dental caries. A cell-envelope stress-sensing histidine kinase, LiaS, is considered to be important for expression of virulence factors such as glucan-binding protein C and mutacin production. In this study, a liaS mutant was subjected to phenotypic microarray (PM) analysis of about 2000 phenotypes, including utilization of various carbon, nitrogen, phosphate and sulfur sources; osmolytes; metabolic inhibitors; and susceptibility to toxic compounds, including several types of antibiotics. Compared to the parental strain UA159, the liaS mutant strain (IBS148) was more tolerant to various inhibitors that target protein synthesis, DNA synthesis and cell-wall biosynthesis. Some of the key findings of the PM analysis were confirmed in independent growth studies and by using antibiotic discs and E-test strips for susceptibility testing.
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