Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice[S]
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 plasm...
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Format: | Article |
Language: | English |
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Elsevier
2009-03-01
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Series: | Journal of Lipid Research |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520308968 |
id |
doaj-c01f6f3ea8d54e55b1a419cd8a290684 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice[S] Journal of Lipid Research hypercholesterolemia mutagenesis ATP binding cassette transporter A1 |
author_facet |
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 |
author_sort |
Todd Juan |
title |
Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice[S] |
title_short |
Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice[S] |
title_full |
Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice[S] |
title_fullStr |
Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice[S] |
title_full_unstemmed |
Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice[S] |
title_sort |
identification of three loci affecting hdl-cholesterol levels in a screen for chemically induced recessive mutations in mice[s] |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2009-03-01 |
description |
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. |
topic |
hypercholesterolemia mutagenesis ATP binding cassette transporter A1 |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520308968 |
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doaj-c01f6f3ea8d54e55b1a419cd8a2906842021-04-28T05:57:14ZengElsevierJournal of Lipid Research0022-22752009-03-01503534545Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice[S]Todd Juan0Murielle M. Véniant1Joan Helmering2Philip Babij3Daniel M. Baker4Michael A. Damore5Michael B. Bass6Tibor Gyuris7Mark Chhoa8Chi-Ming Li9Chris Ebeling10Julie Amato11George A. Carlson12David J. Lloyd13Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405Department 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 23rd Street South, Great Falls, MT 59405We 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.http://www.sciencedirect.com/science/article/pii/S0022227520308968hypercholesterolemiamutagenesisATP binding cassette transporter A1 |