Abstract
Hypercholesterolemia is caused by multiple environmental factors and genetic predispositions, and plays an important role in the development and pathogenesis of various human diseases. In this study, we aimed to establish randomly mutant mouse lines showing hypercholesterolemia for their further use in the detection of novel causative alleles. In the Munich ENU Mouse Mutagenesis Project, clinical chemistry blood analysis was performed on more than 15,000 G1 mice and 230 G3 pedigrees of chemically mutagenized mice to detect dominant and recessive mutations leading to an increased plasma total cholesterol level. Using inbred C3HeB/FeJ mice we identified more than 100 animals consistently showing hypercholesterolemia. Transmission of the altered phenotype to the subsequent generations led to the production of nine hypercholesterolemic lines. A single line showed further obvious deviations in the analysis of additional clinical chemistry blood parameters. Thus, the lines produced will contribute to the search for alleles that selectively cause primary hypercholesterolemia.
Highlights
Hypercholesterolemia is caused by multiple environmental factors and genetic predispositions, and plays an important role in the development and pathogenesis of various human diseases
The search for mutant mice showing increased plasma total cholesterol concentrations in the Munich ENU Mouse Mutagenesis Project was conducted on the inbred C3H genetic background 3 months post partum after overnight fasting of the animals
Of the mice screened for dominant mutations, 60% were male animals; 57 male and 3 female mice showed increased mean plasma total cholesterol levels of the two measurements between 162 mg/dl and 358 mg/dl and between 141 mg/dl and 180 mg/dl, respectively
Summary
Hypercholesterolemia is caused by multiple environmental factors and genetic predispositions, and plays an important role in the development and pathogenesis of various human diseases. A complementary phenotype-driven strategy for the search of the genes involved in the appearance of a defined phenotypic alteration consists of the production of a great pool of randomly mutant mice and the subsequent selection of relevant lines according to the similarities in the pathology of animal model and human patients [1]. Successful detection of the causative mutations in the phenotypically altered mice has been demonstrated in already examined ENU-induced mutant mouse lines [5]. In the Munich ENU Mouse Mutagenesis Project, a screening profile of clinical chemistry blood parameters was established for the analysis of offspring of chemically mutagenized mice in order to detect phenotypic variants with defects of diverse organ systems or changes in metabolic pathways.
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