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

• Published in: Journal of lipid research 2009-03, Vol.50 (3), p.534-545
• Main Authors: Juan, Todd, Véniant, Murielle M., Helmering, Joan, Babij, Philip, Baker, Daniel M., Damore, Michael A., Bass, Michael B., Gyuris, Tibor, Chhoa, Mark, Li, Chi-Ming, Ebeling, Chris, Amato, Julie, Carlson, George A., Lloyd, David J.
• Format: Article
• Language: English
• Subjects: Animals; ATP Binding Cassette Transporter 1; ATP binding cassette transporter A1; ATP-Binding Cassette Transporters - genetics; Base Sequence; CCAAT-Enhancer-Binding Protein-alpha - genetics; Cholesterol - deficiency; Cholesterol, HDL - blood; Cholesterol, HDL - genetics; Chromosome Mapping; DNA - genetics; Ethylnitrosourea - toxicity; Female; Genes, Recessive; Genetic Testing; hypercholesterolemia; Hyperlipoproteinemia Type II - blood; Hyperlipoproteinemia Type II - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutagenesis; Mutagens - toxicity; Mutation; Mutation, Missense; Phenotype; Polymorphism, Single Nucleotide
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M800471-JLR200

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.