Abstract
BackgroundPreviously, we identified three loci affecting HDL-cholesterol levels in a screen for ENU-induced mutations in mice and discovered two mutated genes. We sought to identify the third mutated gene and further characterize the mouse phenotype.MethodsWe engaged, DNA sequencing, gene expression profiling, western blotting, lipoprotein characterization, metabolomics assessment, histology and electron microscopy in mouse tissues.ResultsWe identify the third gene as Ampd2, a liver isoform of AMP Deaminase (Ampd), a central component of energy and purine metabolism pathways. The causative mutation was a guanine-to-thymine transversion resulting in an A341S conversion in Ampd2. Ampd2 homozygous mutant mice exhibit a labile hypercholesterolemia phenotype, peaking around 9 weeks of age (251 mg/dL vs. wildtype control at 138 mg/dL), and was evidenced by marked increases in HDL, VLDL and LDL. In an attempt to determine the molecular connection between Ampd2 dysfunction and hypercholesterolemia, we analyzed hepatic gene expression and found the downregulation of Ldlr, Hmgcs and Insig1 and upregulation of Cyp7A1 genes. Metabolomic analysis confirmed an increase in hepatic AMP levels and a decrease in allantoin levels consistent with Ampd2 deficiency, and increases in campesterol and β-sitosterol. Additionally, nephrotic syndrome was observed in the mutant mice, through proteinuria, kidney histology and effacement and blebbing of podocyte foot processes by electron microscopy.ConclusionIn summary we describe the discovery of a novel genetic mouse model of combined transient nephrotic syndrome and hypercholesterolemia, resembling the human disorder.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-511X-13-167) contains supplementary material, which is available to authorized users.
Highlights
Hypercholesterolemia is a major risk factor for developing coronary artery disease, the most common cause for heart disease and the leading cause of death worldwide
We identify the mutation as a recessive loss of function missense mutation in the gene encoding adenosine monophosphate deaminase 2 (Ampd2)
Hepatic gene expression analysis of Ampd2 mice In an attempt to uncover a pathogenic mechanism for the observed hypercholesterolemia we focused our attention on liver lipid metabolism
Summary
Hypercholesterolemia is a major risk factor for developing coronary artery disease, the most common cause for heart disease and the leading cause of death worldwide. Coronary artery disease occurs when excess cholesterol in the bloodstream accumulates and forms plaques in the coronary arteries. This narrowing and hardening of the arteries can eventually lead to myocardial infarction. One line of mice presented undetectable levels of HDL-C, caused by a missense mutation in the ATP binding cassette transporter A1 (Abca1) gene. The second line of mice which had very high levels of plasma total cholesterol and HDL-C was mapped to a missense mutation in CCAAT/enhancer binding protein α (C/ebpα). A third line of mice was characterized with a reduced penetrance labile hypercholesterolemia phenotype but the underlying mutation had not been identified. We identified three loci affecting HDL-cholesterol levels in a screen for ENU-induced mutations in mice and discovered two mutated genes. We sought to identify the third mutated gene and further characterize the mouse phenotype
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