BACKGROUND: We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene. METHODS AND RESULTS: We first fine-mapped the locus by studying a series of congenic strains derived from the parental strains BALB/cJ and MRL/MpJ. Analysis of gene expression and sequencing followed by transgenic complementation led to the identification of zinc fingers and homeoboxes 2 (Zhx2), a transcription factor previously implicated in the developmental regulation of alpha-fetoprotein. Reduced expression of the protein in BALB/cJ mice resulted in altered hepatic transcript levels for several genes involved in lipoprotein metabolism. Most notably, the Zhx2 mutation resulted in a failure to suppress expression of lipoprotein lipase, a gene normally silenced in the adult liver, and this was normalized in BALB/cJ mice carrying the Zhx2 transgene. CONCLUSIONS: We identified the gene underlying the chromosome 15 quantitative trait locus, and our results show that Zhx2 functions as a novel developmental regulator of key genes influencing lipoprotein metabolism.
BACKGROUND: We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene. METHODS AND RESULTS: We first fine-mapped the locus by studying a series of congenic strains derived from the parental strains BALB/cJ and MRL/MpJ. Analysis of gene expression and sequencing followed by transgenic complementation led to the identification of zinc fingers and homeoboxes 2 (Zhx2), a transcription factor previously implicated in the developmental regulation of alpha-fetoprotein. Reduced expression of the protein in BALB/cJ mice resulted in altered hepatic transcript levels for several genes involved in lipoprotein metabolism. Most notably, the Zhx2 mutation resulted in a failure to suppress expression of lipoprotein lipase, a gene normally silenced in the adult liver, and this was normalized in BALB/cJ mice carrying the Zhx2 transgene. CONCLUSIONS: We identified the gene underlying the chromosome 15 quantitative trait locus, and our results show that Zhx2 functions as a novel developmental regulator of key genes influencing lipoprotein metabolism.
Authors: Jose M Ordovas; Dolores Corella; Serkalem Demissie; L Adrienne Cupples; Patrick Couture; Oscar Coltell; Peter W F Wilson; Ernst J Schaefer; Katherine L Tucker Journal: Circulation Date: 2002-10-29 Impact factor: 29.690
Authors: T G Kirchgessner; R C LeBoeuf; C A Langner; S Zollman; C H Chang; B A Taylor; M C Schotz; J I Gordon; A J Lusis Journal: J Biol Chem Date: 1989-01-25 Impact factor: 5.157
Authors: Stephania A Cormier; Shubing Yuan; Jeffrey R Crosby; Cheryl A Protheroe; Dawn M Dimina; Edith M Hines; Nancy A Lee; James J Lee Journal: Am J Respir Cell Mol Biol Date: 2002-12 Impact factor: 6.914
Authors: Christopher T Johansen; Jian Wang; Adam D McIntyre; Rebecca A Martins; Matthew R Ban; Matthew B Lanktree; Murray W Huff; Miklós Péterfy; Margarete Mehrabian; Aldons J Lusis; Sekar Kathiresan; Sonia S Anand; Salim Yusuf; Ann-Hwee Lee; Laurie H Glimcher; Henian Cao; Robert A Hegele Journal: Circ Cardiovasc Genet Date: 2011-12-01
Authors: Inna G Ovsyannikova; Richard B Kennedy; Megan O'Byrne; Robert M Jacobson; V Shane Pankratz; Gregory A Poland Journal: Vaccine Date: 2012-04-25 Impact factor: 3.641