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Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 I27N mutant mice.

ABSTRACT: 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 dominant mutant line HST014 was established and further analyzed.Analysis of the causative mutation as well as the standardized, systemic phenotypic analysis of the mutant line was carried out.The 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.In 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.

SUBMITTER: Kumar S

PROVIDER: S-EPMC5559776 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 <sup>I27N</sup> mutant mice.

Kumar Sudhir S Rathkolb Birgit B Sabrautzki Sibylle S Krebs Stefan S Kemter Elisabeth E Becker Lore L Beckers Johannes J Bekeredjian Raffi R Brommage Robert R Calzada-Wack Julia J Garrett Lillian L Hölter Sabine M SM Horsch Marion M Klingenspor Martin M Klopstock Thomas T Moreth Kristin K Neff Frauke F Rozman Jan J Fuchs Helmut H Gailus-Durner Valérie V Hrabe de Angelis Martin M Wolf Eckhard E Aigner Bernhard B

Journal of biomedical science 20170817 1

<h4>Background</h4>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 dominant mutant line HST014 was established and further analyzed.<h4>Methods</h4>Analysis of the causative mutation as well as the standardized, systemic phenotypic analysis of the mutant line was carried out.<h4>Results</h4>Th ...[more]

PMID: 28818080

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Project description:Epigenetic processes including RNA methylation, post-translational modifications, and non-coding RNA expression have been associated with the heritable risks of systemic lupus erythematosus (SLE). In this study, we aimed to explore the dysregulated expression of 5-methylcytosine (m5C) in CD4+ T cells from patients with SLE and the potential function of affected mRNAs in SLE pathogenesis. mRNA methylation profiles were ascertained through chromatography-coupled triple quadrupole mass spectrometry in CD4+ T cells from two pools of patients with SLE exhibiting stable activity, two pools with moderate-to-major activity, and two pools of healthy controls (HCs). Simultaneously, mRNA methylation profiles and expression profiling were performed using RNA-Bis-Seq and RNA-Seq, respectively. Integrated mRNA methylation and mRNA expression bioinformatics analysis was comprehensively performed. mRNA methyltransferase NSUN2 expression was validated in CD4+ T cells from 27 patients with SLE and 28 HCs using real-time polymerase chain reaction and western blot analyses. Hypomethylated-mRNA profiles of NSUN2-knockdown HeLa cells and of CD4+ T cells of patients with SLE were jointly analyzed using bioinformatics. Eleven methylation modifications (including elevated Am, 3'OMeA, m1A, and m6A and decreased Ψ, m3C, m1G, m5U, and t6A levels) were detected in CD4+ T cells of patients with SLE. Additionally, decreased m5C levels, albeit increased number of m5C-containing mRNAs, were observed in CD4+ T cells of patients with SLE compared with that in CD4+ T cells of HCs. m5C site distribution in mRNA transcripts was highly conserved and enriched in mRNA translation initiation sites. In particular, hypermethylated m5C or/and significantly up-regulated genes in SLE were significantly involved in immune-related and inflammatory pathways, including immune system, cytokine signaling pathway, and interferon signaling. Compared to that in HCs, NSUN2 expression was significantly lower in SLE CD4+ T cells. Notably, hypomethylated m5C genes in SLE and in NSUN2-knockdown HeLa cells revealed linkage between eukaryotic translation elongation and termination, and mRNA metabolism. Our study identified novel aberrant m5C mRNAs relevant to critical immune pathways in CD4+ T cells from patients with SLE. These data provide valuable perspectives for future studies of the multifunctionality and post-transcriptional significance of mRNA m5C modification in SLE.

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Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 I27N mutant mice.

Publications

Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 <sup>I27N</sup> mutant mice.

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