| First Author | Sabbagha NG | Year | 2011 |
| Journal | Pediatr Res | Volume | 70 |
| Issue | 1 | Pages | 31-6 |
| PubMed ID | 21659959 | Mgi Jnum | J:222356 |
| Mgi Id | MGI:5644397 | Doi | 10.1203/PDR.0b013e31821b89ee |
| Citation | Sabbagha NG, et al. (2011) Alternative splicing in Acad8 resulting a mitochondrial defect and progressive hepatic steatosis in mice. Pediatr Res 70(1):31-6 |
| abstractText | 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. |
