title: A mutation in Ampd2 is associated with nephrotic syndrome and hypercholesterolemia in mice.
abstract: BACKGROUND
  Previously, 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.
  
  
  METHODS
  We engaged, DNA sequencing, gene expression profiling, western blotting, lipoprotein characterization, metabolomics assessment, histology and electron microscopy in mouse tissues.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  In summary we describe the discovery of a novel genetic mouse model of combined transient nephrotic syndrome and hypercholesterolemia, resembling the human disorder.
authors.forename: Joan
authors.initials: J
authors.lastname: Helmering
authors.forename: Todd
authors.initials: T
authors.lastname: Juan
authors.forename: Chi Ming
authors.initials: CM
authors.lastname: Li
authors.forename: Mark
authors.initials: M
authors.lastname: Chhoa
authors.forename: Will
authors.initials: W
authors.lastname: Baron
authors.forename: Tibor
authors.initials: T
authors.lastname: Gyuris
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.forename: James R
authors.initials: JR
authors.lastname: Turk
authors.forename: Jeff
authors.initials: J
authors.lastname: Lawrence
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Cosgrove
authors.forename: Jim
authors.initials: J
authors.lastname: Busby
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Kaufman
authors.forename: Connie
authors.initials: C
authors.lastname: Cummings
authors.forename: George
authors.initials: G
authors.lastname: Carlson
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Véniant
authors.affiliation: Department of Metabolic Disorders, Amgen Inc, One Amgen Center Dr, Thousand Oaks, CA 91320, USA. dlloyd@amgen.com.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lloyd
mesh_terms: D000659:AMP Deaminase / Q000235:genetics*; D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood; D015870:Gene Expression; D056726:Genetic Association Studies; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics*; D007678:Kidney Glomerulus / Q000473:pathology; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000097:blood / Q000235:genetics*; D011507:Proteinuria / Q000097:blood / Q000235:genetics
chemical_list: D008076:Cholesterol, HDL; D000659:AMP Deaminase; C000592119:AMPD2 protein, mouse