Alternative splicing in Acad8 resulting a mitochondrial defect and progressive hepatic steatosis in mice.

Journal Article (Journal Article)

Using a combination of N-ethyl-N-nitrosourea-mediated mutagenesis and metabolomics-guided screening, we identified mice with elevated blood levels of short-chain C4-acylcarnitine and increased urine isobutyryl-glycine. Genome-wide homozygosity screening, followed by fine mapping, located the disease gene to 15-25 Mb of mouse chromosome 9 where a candidate gene, Acad8, encoding mitochondrial isobutyryl-CoA dehydrogenase was located. Genomic DNA sequencing revealed a single-nucleotide mutation at -17 of the first intron of Acad8 in affected mice. cDNA sequencing revealed an intronic 28-bp insertion at the site of the mutation, which caused a frame shift with a premature stop codon. In vitro splicing assay confirmed that the mutation was sufficient to activate an upstream, aberrant 3' splice site. There was a reduction in the expression of Acad8 at both the mRNA and protein levels. The mutant mice grew normally but demonstrated cold intolerance at young age with a progressive hepatic steatosis. Homozygous mutant mice hepatocytes had abnormal mitochondria with crystalline inclusions, suggestive of mitochondriopathy. This mouse model of isobutyryl-CoA dehydrogenase deficiency could provide us a better understanding of the possible role of IBD deficiency in mitochondriopathy and fatty liver.

Full Text

Duke Authors

Cited Authors

  • Sabbagha, NGAA-A; Kao, H-J; Yang, C-F; Huang, C-C; Lin, W-D; Tsai, F-J; Chen, T-H; Tarn, W-Y; Wu, J-Y; Chen, Y-T

Published Date

  • July 2011

Published In

Volume / Issue

  • 70 / 1

Start / End Page

  • 31 - 36

PubMed ID

  • 21659959

Electronic International Standard Serial Number (EISSN)

  • 1530-0447

Digital Object Identifier (DOI)

  • 10.1203/PDR.0b013e31821b89ee


  • eng

Conference Location

  • United States