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

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, and David J. Llloyd

Metabolic Disorders, Amgen Inc., Thousand Oaks, CA 91320

Corresponding Author: dlloyd{at}amgen.com

We conducted a genome-wide screen using the mutagen N-ethyl-N-nitrosourea (ENU) to identify recessive mutations in genes which lead to altered lipid traits in mice. We screened 7546 G3 mice which were of mixed C57BL/6J (B6) x C3.SW-H2^b/SnJ (C3) genomes and identified 3 pedigrees with differences in plasma high-density lipoprotein (HDL) cholesterol. Genome-scan analyses mapped 3 distinct loci to chromosomes 3, 4 and 7. A S1748L missense mutation was identified in ATP-binding cassette transporter A1 (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- 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 $alpha$ (C/EBP $alpha$ ). Lastly, 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 3 novel alleles of HDL-cholesterol phenotypes.

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