Dataset Information

Farp2 and Stk25 are candidate genes for the HDL cholesterol locus on mouse chromosome 1.

ABSTRACT: To identify the gene responsible for the quantitative trait locus (QTL) Hdlq14, a high-density lipoprotein cholesterol (HDL) QTL previously identified in a C57BL/6Jx129S1/SvImJ cross.Hdlq14 was first confirmed as an independent QTL by detecting it in an intercross between NZB/B1NJ and NZW/LacJ, 2 strains that had identical genotypes at nearby QTL genes on chromosome 1. Using the bioinformatics tools of combined cross data and haplotype analysis, we narrowed this QTL from a 45-Mb 225-gene region to 2 genes, Farp2 and Stk25. Sequencing and expression studies showed that Farp2 had an amino acid polymorphism in an important plekstrin domain and that Stk25 had a significant expression difference between the parental strains. These 2 genes are immediately adjacent to each other and share the same haplotype over 45 inbred strains. The haplotype was associated with a significant difference in HDL levels among these strains.We confirmed Hdlq14 as a separate independent QTL for HDL and narrowed the region to 2 genes, Farp2 and Stk25, with considerable evidence for both. Additional studies are needed to choose between these 2 genes or to show that both are important in determining HDL levels.

SUBMITTER: Su Z

PROVIDER: S-EPMC2782635 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Farp2 and Stk25 are candidate genes for the HDL cholesterol locus on mouse chromosome 1.

Su Zhiguang Z Cox Allison A Shen Yuan Y Stylianou Ioannis M IM Paigen Beverly B

Arteriosclerosis, thrombosis, and vascular biology 20081106 1

<h4>Objective</h4>To identify the gene responsible for the quantitative trait locus (QTL) Hdlq14, a high-density lipoprotein cholesterol (HDL) QTL previously identified in a C57BL/6Jx129S1/SvImJ cross.<h4>Methods and results</h4>Hdlq14 was first confirmed as an independent QTL by detecting it in an intercross between NZB/B1NJ and NZW/LacJ, 2 strains that had identical genotypes at nearby QTL genes on chromosome 1. Using the bioinformatics tools of combined cross data and haplotype analysis, we n ...[more]

PMID: 18988887

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Project description:Despite considerable progress understanding genes that affect the HDL particle, its function, and cholesterol content, genes identified to date explain only a small percentage of the genetic variation. We used N-ethyl-N-nitrosourea mutagenesis in mice to discover novel genes that affect HDL cholesterol levels. Two mutant lines (Hlb218 and Hlb320) with low HDL cholesterol levels were established. Causal mutations in these lines were mapped using linkage analysis: For line Hlb218 within a 12 Mbp region on Chr 10; and for line Hlb320 within a 17 Mbp region on Chr 7. High-throughput sequencing of Hlb218 liver RNA identified a mutation in Pla2g12b. The transition of G to A leads to a cysteine to tyrosine change and most likely causes a loss of a disulfide bridge. Microarray analysis of Hlb320 liver RNA showed a 7-fold downregulation of Hpn; sequencing identified a mutation in the 3M-bM-^@M-2 splice site of exon 8. Northern blot confirmed lower mRNA expression level in Hlb320 and did not show a difference in splicing, suggesting that the mutation only affects the splicing rate. In addition to affecting HDL cholesterol, the mutated genes also lead to reduction in serum non-HDL cholesterol and triglyceride levels. Despite low HDL cholesterol levels, the mice from both mutant lines show similar atherosclerotic lesion sizes compared to control mice. These new mutant mouse models are valuable tools to further study the role of these genes, their affect on HDL cholesterol levels, and metabolism. Mutant mice were generated as part of The Jackson LaboratoryM-bM-^@M-^Ys Heart, Lung, Blood, and Sleep Disorder Mutagenesis Program by treating male C57BL/6J (B6) mice with N-ethyl-N-nitrosourea (ENU). Third generation (G3) mice were phenotyped to ensure capture of both dominant and recessive mutations. Two unique G3 animals with low HDL cholesterol levels were then used to establish new inbred lines (Hlb218 and Hlb320) by mating them with B6 mice and intercrossing the offspring with low HDL cholesterol for 7 generations. Livers from 3 Hlb218, 3 Hlb320 males, and 6 B6 male controls were obtained for gene expression analysis. The samples were randomized over Illumina Mouse-6 Expression 1.1 BeadChips .

Dataset Information

Farp2 and Stk25 are candidate genes for the HDL cholesterol locus on mouse chromosome 1.

Publications

Farp2 and Stk25 are candidate genes for the HDL cholesterol locus on mouse chromosome 1.

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