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Lampe1: an ENU-germline mutation causing spontaneous hepatosteatosis identified through targeted exon-enrichment and next-generation sequencing.

Using a small scale ENU mutagenesis approach we identified a recessive germline mutant, designated Lampe1 that exhibited growth retardation and spontaneous hepatosteatosis. Low resolution mapping based on 20 intercrossed Lampe1 mice revealed linkage to a ∼14 Mb interval on the distal site of chromosome 11 containing a total of 285 genes. Exons and 50 bp flanking sequences within the critical region were enriched with sequence capture microarrays and subsequently analyzed by next-generation sequencing. Using this approach 98.1 percent of the targeted DNA was covered with a depth of 10 or more reads per nucleotide and 3 homozygote mutations were identified. Two mutations represented intronic nucleotide changes whereas one mutation affected a splice donor site in intron 11-12 of Palmitoyl Acetyl-coenzyme A oxygenase-1 (Acox1), causing skipping of exon 12. Phenotyping of Acox1(Lampe1) mutants revealed a progression from hepatosteatosis to steatohepatitis, and ultimately hepatocellular carcinoma. The current approach provides a highly efficient and affordable method to identify causative mutations induced by ENU mutagenesis and animal models relevant to human pathology.

Pubmed ID: 21760938

Authors

  • Sheridan R
  • Lampe K
  • Shanmukhappa SK
  • Putnam P
  • Keddache M
  • Divanovic S
  • Bezerra J
  • Hoebe K

Journal

PloS one

Publication Data

July 15, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P30 DK078392
  • Agency: PHS HHS, Id: R01 00426912
  • Agency: PHS HHS, Id: R21 00290411

Mesh Terms

  • Animals
  • Ethylnitrosourea
  • Exons
  • Fatty Liver
  • Gene Targeting
  • Germ-Line Mutation
  • Humans
  • Lipid Metabolism
  • Liver
  • Liver Neoplasms
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Phenotype
  • RNA Splice Sites
  • Sequence Analysis, DNA
  • Sequence Deletion