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

• Main Authors: Todd Juan, Murielle M. Véniant, Joan Helmering, Philip Babij, Daniel M. Baker, Michael A. Damore, Michael B. Bass, Tibor Gyuris, Mark Chhoa, Chi-Ming Li, Chris Ebeling, Julie Amato, George A. Carlson, David J. Lloyd
• Format: Article
• Language: English
• Published: Elsevier 2009-03-01
• Series: Journal of Lipid Research
• Subjects: hypercholesterolemia; mutagenesis; ATP binding cassette transporter A1
• Online Access: http://www.sciencedirect.com/science/article/pii/S0022227520308968

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)×C3.SW-H2b/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, semi-dominant, 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 α (C/EBPα). 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.