Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice[S]
| Autor: | Daniel M. Baker, George A. Carlson, Murielle M. Véniant, Mark Chhoa, Julie Amato, Michael Bass, Chi-Ming Li, Philip Babij, Michael A. Damore, Joan Helmering, Chris Ebeling, David Lloyd, Tibor Gyuris, Todd Juan |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
Mutation Missense Genes Recessive Locus (genetics) QD415-436 Biology Polymorphism Single Nucleotide Biochemistry Hyperlipoproteinemia Type II Mice Endocrinology Enhancer binding CCAAT-Enhancer-Binding Protein-alpha Animals Missense mutation Genetic Testing Allele Gene Genetics Base Sequence hypercholesterolemia Cholesterol HDL Chromosome Mapping DNA Cell Biology Molecular biology Penetrance Phenotype Mice Mutant Strains Mice Inbred C57BL Cholesterol Chromosome 3 Ethylnitrosourea Mutation ATP-Binding Cassette Transporters Female lipids (amino acids peptides and proteins) ATP binding cassette transporter A1 mutagenesis ATP Binding Cassette Transporter 1 Mutagens |
| Zdroj: | Journal of Lipid Research, Vol 50, Iss 3, Pp 534-545 (2009) |
| ISSN: | 0022-2275 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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