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 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.
Highlights
Biomedical research with mice as animal models includes the search for and the analysis of alleles that predispose for or protect against specific diseases
The ENU mutagenesis-derived, recessive mutant line HST011 with the G1 male founder ID 20033899 was established on the C3H inbred genetic background by showing increased plasma urea values at the age of three months in homozygous mutant mice
The candidate gene Pou3f3 was selected for the sequence analysis, as it is located at 42.7 Mb on chromosome 1, and a published mutant phenotype has been described with increased plasma urea and potassium levels associated with renal hypoplasia
Summary
Biomedical research with mice as animal models includes the search for and the analysis of alleles that predispose for or protect against specific diseases. A strategy for the search of novel disease-related alleles consists of the random chemical mutagenesis of a large number of animals followed by the systematic screening for clinically relevant disease phenotypes. In the phenotype-driven Munich ENU mouse mutagenesis project using C3HeB/FeJ (C3H) inbred mice as genetic background, a standardized screening profile of clinical chemical blood plasma parameters was established for the analysis of the offspring of the mutagenized mice in order to detect phenotypic variants [2,3]. Several mutant lines were established showing increased plasma urea levels as a parameter that is indicative of kidney diseases [4]
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