Gargalovic Peter S, Erbilgin Ayça, Kohannim Omid, Pagnon Joanne, Wang Xuping, Castellani Lawrence, LeBoeuf Renee, Peterson Martha L, Spear Brett T, Lusis Aldons J
Department of Medicine, Microbiology, University of California, Los Angeles, CA 90095-1679, USA.
Circ Cardiovasc Genet. 2010 Feb;3(1):60-7. doi: 10.1161/CIRCGENETICS.109.902320. Epub 2009 Dec 30.
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.
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.
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.
我们之前在小鼠的15号染色体上定位了一个影响高密度脂蛋白胆固醇和甘油三酯水平的数量性状基因座，现在报告该基因座相关基因的鉴定结果。
我们首先通过研究一系列源自亲本品系BALB/cJ和MRL/MpJ的近交系来精细定位该基因座。通过基因表达分析、测序以及转基因互补实验，我们鉴定出了锌指和同源盒2（Zhx2）基因，这是一种先前被认为与甲胎蛋白发育调控有关的转录因子。BALB/cJ小鼠中该蛋白表达降低导致了几个参与脂蛋白代谢的基因的肝脏转录水平发生改变。最显著的是，Zhx2突变导致无法抑制脂蛋白脂肪酶的表达，该基因在成年肝脏中通常是沉默的，而携带Zhx2转基因的BALB/cJ小鼠中这种情况得到了正常化。
我们鉴定出了15号染色体数量性状基因座相关的基因，我们的结果表明Zhx2作为一种新型的发育调节因子，对影响脂蛋白代谢的关键基因发挥作用。
