A mutation in Ampd2 is associated with nephrotic syndrome and hypercholesterolemia in mice

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.

Network analysis of membranous glomerulonephritis based on metabolomics data

“…AMP deaminase (Ampd) is the rate-limiting enzyme in the catabolism of AMP to uric acid and is a component of the purine nucleotide cycle, which is responsible for the deamination of AMP to inosine monophosphate ( 61 ). Helmering et al ( 61 ) reported that a mutation in the Ampd2 gene (a liver isoform of Ampd ) leads to nephrotic syndrome and hypercholesterolemia in Ampd2 knockout (KO) mice.…”

“…AMP deaminase (Ampd) is the rate-limiting enzyme in the catabolism of AMP to uric acid and is a component of the purine nucleotide cycle, which is responsible for the deamination of AMP to inosine monophosphate ( 61 ). Helmering et al ( 61 ) reported that a mutation in the Ampd2 gene (a liver isoform of Ampd ) leads to nephrotic syndrome and hypercholesterolemia in Ampd2 knockout (KO) mice. It was additionally observed that the Ampd2 KO mice had minimal alterations in the kidneys, minimal to moderate thickening of the GBM, an increase in the cellularity of the mesangial matrix and an increase in inflammatory cells in the glomeruli.…”

Novel AMPD2 mutation in pontocerebellar hypoplasia, dysmorphisms, and teeth abnormalities

“… 2 , 6 Recently, AMPD2 mutant mice and Ampd2−/− mice have been associated with nephrotic syndrome and proteinuria in the absence of any brain abnormality. 7 A neurodegenerative phenotype has been observed when both Ampd2 and Ampd3 are knocked out, suggesting a functional redundancy among AMP deaminase homologs. However, it remains to be elucidated whether humans carrying AMPD2 mutations may have renal involvement.…”

Overexpression of AMPD2 indicates poor prognosis in colorectal cancer patients via the Notch3 signaling pathway

“…AMPD2 is an important enzyme involved in adenosine monophosphate metabolism and plays an important biological function in adenylate metabolism in smooth muscle tissue[ 7 ]. In previous studies, it was shown that AMPD2 affected the nephrotic syndrome and hypercholesterolemia[ 8 ]. In addition, it has been demonstrated that AMPD2 dramatically affected physiological and pathological processes[ 9 ].…”