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. Lloyd¹^,*

^* Department of Metabolic Disorders, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320
Department of Protein Sciences, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320
Department of Molecular Sciences, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320
^** Department of Computational Biology, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320
McLaughlin Research Institute, 1520 23^rd Street South, Great Falls, MT 59405

The online version of this article (available at http://www.jlr.org)contains supplementary data in the form of two tables.

Published, JLR Papers in Press, October 30, 2008.

^¹ To whom correspondence should be addressed. e-mail: dlloyd{at}amgen.com

We conducted a genome-wide screen using the mutagen N-ethyl-N-nitrosoureato identify recessive mutations in genes that lead to alteredlipid traits in mice. We screened 7,546 G3 mice that were ofmixed C57BL/6J (B6)xC3.SW-H2^b/SnJ (C3) genomes and identifiedthree pedigrees with differences in plasma HDL-cholesterol.Genome scan analyses mapped three distinct loci to chromosomes3, 4, and 7. An S1748L missense mutation was identified in ABCA1in one pedigree with undetectable levels of HDL-cholesteroland resulted in reduced protein levels. This phenotype was completelypenetrant, semi-dominant, and cosegregated with high plasmatriglycerides. Mice in a second pedigree had very high levelsof plasma total cholesterol and HDL-cholesterol (up to 800 mg/dltotal cholesterol). Despite a high degree of phenotype labilityand reduced penetrance, an I68N missense mutation was identifiedin the transcription factor CCAAT/enhancer binding protein ${alpha}$ (C/EBP ${alpha}$ ). Finally, a second high HDL-cholesterol pedigree ofmice, again with a highly labile phenotype and reduced penetrance,was mapped to a 7 Mb locus on chromosome 3. These results illustratethe use of a hybrid background for simultaneous screening andmapping of mutagenized pedigrees of mice and identificationof three novel alleles of HDL-cholesterol phenotypes.

Supplementary key words hypercholesterolemia • mutagenesis • ATP binding cassette transporter A1

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