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, 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 alpha (C/EBPalpha). 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
Todd
T
Department of Protein Sciences, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320.
Véniant
Murielle M
MM
Department of Metabolic Disorders, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320.
Helmering
Joan
J
Department of Metabolic Disorders, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320.
Babij
Philip
P
Department of Metabolic Disorders, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320.
Baker
Daniel M
DM
Department of Molecular Sciences, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320.
Damore
Michael A
MA
Department of Molecular Sciences, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320.
Bass
Michael B
MB
Department of Computational Biology, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320.
Gyuris
Tibor
T
Department of Protein Sciences, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320.
Chhoa
Mark
M
Department of Protein Sciences, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320.
Li
Chi-Ming
CM
Department of Protein Sciences, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320.
Ebeling
Chris
C
McLaughlin Research Institute, 1520 23rd Street South, Great Falls, MT 59405.
Amato
Julie
J
McLaughlin Research Institute, 1520 23rd Street South, Great Falls, MT 59405.
Carlson
George A
GA
McLaughlin Research Institute, 1520 23rd Street South, Great Falls, MT 59405.
Lloyd
David J
DJ
Department of Metabolic Disorders, Amgen, Inc., One Amgen Centre Drive, Thousand Oaks, CA 91320. Electronic address: dlloyd@amgen.com.
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D002784:Cholesterol / Q000172:deficiency; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics*; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D005808:Genes, Recessive; D005820:Genetic Testing; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D022763:CCAAT-Enhancer-Binding Protein-alpha; D008076:Cholesterol, HDL; D009153:Mutagens; D004247:DNA; D002784:Cholesterol; D005038:Ethylnitrosourea