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

Publication ,  Journal Article
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 in: Pediatr Res
July 2011

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.

Duke Scholars

Published In

Pediatr Res

DOI

EISSN

1530-0447

Publication Date

July 2011

Volume

70

Issue

1

Start / End Page

31 / 36

Location

United States

Related Subject Headings

  • Thermosensing
  • Thermogenesis
  • RNA, Messenger
  • Phenotype
  • Pediatrics
  • PPAR gamma
  • PPAR alpha
  • Oxidoreductases Acting on CH-CH Group Donors
  • Orphan Nuclear Receptors
  • Mutation
 

Citation

APA
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Sabbagha, N.-A., Kao, H.-J., Yang, C.-F., Huang, C.-C., Lin, W.-D., Tsai, F.-J., … Chen, Y.-T. (2011). Alternative splicing in Acad8 resulting a mitochondrial defect and progressive hepatic steatosis in mice. Pediatr Res, 70(1), 31–36. https://doi.org/10.1203/PDR.0b013e31821b89ee
Sabbagha, Nagham George Abd Al-Ahad, Hsiao-Jung Kao, Chih-Fu Yang, Cheng-Chih Huang, Wei-De Lin, Fuu-Jen Tsai, Tzu-Ho Chen, Woan-Yuh Tarn, Jer-Yuarn Wu, and Yuan-Tsong Chen. “Alternative splicing in Acad8 resulting a mitochondrial defect and progressive hepatic steatosis in mice.Pediatr Res 70, no. 1 (July 2011): 31–36. https://doi.org/10.1203/PDR.0b013e31821b89ee.
Sabbagha NGAA-A, Kao H-J, Yang C-F, Huang C-C, Lin W-D, Tsai F-J, et al. Alternative splicing in Acad8 resulting a mitochondrial defect and progressive hepatic steatosis in mice. Pediatr Res. 2011 Jul;70(1):31–6.
Sabbagha, Nagham George Abd Al-Ahad, et al. “Alternative splicing in Acad8 resulting a mitochondrial defect and progressive hepatic steatosis in mice.Pediatr Res, vol. 70, no. 1, July 2011, pp. 31–36. Pubmed, doi:10.1203/PDR.0b013e31821b89ee.
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. Alternative splicing in Acad8 resulting a mitochondrial defect and progressive hepatic steatosis in mice. Pediatr Res. 2011 Jul;70(1):31–36.

Published In

Pediatr Res

DOI

EISSN

1530-0447

Publication Date

July 2011

Volume

70

Issue

1

Start / End Page

31 / 36

Location

United States

Related Subject Headings

  • Thermosensing
  • Thermogenesis
  • RNA, Messenger
  • Phenotype
  • Pediatrics
  • PPAR gamma
  • PPAR alpha
  • Oxidoreductases Acting on CH-CH Group Donors
  • Orphan Nuclear Receptors
  • Mutation