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Kumar, Sudhir; Rathkolb, Birgit; Sabrautzki, Sibylle; Krebs, Stefan; Kemter, Elisabeth; Becker, Lore; Beckers, Johannes; Bekeredjian, Raffi; Brommage, Robert; Calzada-Wack, Julia; Garrett, Lillian; Hölter, Sabine M.; Horsch, Marion; Klingenspor, Martin; Klopstock, Thomas; Moreth, Kristin; Neff, Frauke; Rozman, Jan; Fuchs, Helmut; Gailus-Durner, Valerie; Hrabe de Angelis, Martin; Wolf, Eckhard; Aigner, Bernhard (2017): Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1(I27N) mutant mice. In: Journal of Biomedical Science 24:57


Background: 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. Methods: Analysis of the causative mutation as well as the standardized, systemic phenotypic analysis of the mutant line was carried out. Results: 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. Genomewide 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. Conclusions: 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.