Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice

We conducted a genome-wide screen using the mutagen N-ethyl-N-nitrosourea to identify recessive mutations in genes that lead to altered lipid traits in mice. We screened 7,546 G3 mice that were of mixed C57BL/6J (B6) x C3.SW-H2(b)/SnJ (C3) genomes and identified three pedigrees with differences in plasma HDL-cholesterol. Genome scan analyses mapped three distinct loci to chromosomes 3, 4, and 7. An S1748L missense mutation was identified in ABCA1 in one pedigree with undetectable levels of HDL-cholesterol and resulted in reduced protein levels. This phenotype was completely penetrant, semidominant, and cosegregated with high plasma triglycerides. Mice in a second pedigree had very high levels of plasma total cholesterol and HDL-cholesterol (up to 800 mg/dl total cholesterol). Despite a high degree of phenotype lability and reduced penetrance, an I68N missense mutation was identified in the transcription factor CCAAT/enhancer binding protein a (C/EBP alpha). Finally, a second high HDL-cholesterol pedigree of mice, again with a highly labile phenotype and reduced penetrance, was mapped to a 7 Mb locus on chromosome 3. These results illustrate the use of a hybrid background for simultaneous screening and mapping of mutagenized pedigrees of mice and identification of three novel alleles of HDL-cholesterol phenotypes.-Juan, T., M. M. Veniant, J. Helmering, P. Babij, D. M. Baker, M. A. Damore, M. B. Bass, T. Gyuris, M. Chhoa, C-M. Li, C. Ebeling, J. Amato, G. A. Carlson, and D. J. Lloyd. Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice. J. Lipid Res. 2009. 50: 534-545.