Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse

Keith B. Cox, Doug A. Hamm, David S. Millington, Dietrich Matern, Jerry Vockley, Piero Rinaldo, Carl A. Pinkert, William J. Rhead, J. Russell Lindsey, Philip A. Wood

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93 Scopus citations

Abstract

Although many patients have been found to have very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, none have been documented with long-chain acyl-CoA dehydrogenase (LCAD) deficiency. In order to understand the metabolic pathogenesis of long-chain fatty acid oxidation disorders, we generated mice with VLCAD deficiency (VLCAD-/-) and compared their pathologic and biochemical phenotypes of mice with LCAD deficiency (LCAD-/-) and wild-type mice. VLCAD-/- mice had milder fatty change in liver and heart. Dehydrogenation of various acyl-CoA substrates by liver, heart and skeletal muscle mitochondria differed among the three genotypes. The results for liver were most informative as VLCAD-/- mice had a reduction in activity toward palmitoyl-CoA and oleoyl-CoA (58 and 64% of wild-type, respectively), whereas LCAD-/- mice showed a more profoundly reduced activity toward these substrates (35 and 32% of wild-type, respectively), with a significant reduction of activity toward the branched chain substrate 2,6-dimethylheptanoyl-CoA. C16 and C18 acylcarnitines were elevated in bile, blood and serum of fasted VLCAD-/- mice, whereas abnormally elevated C12 and C14 acylcarnitines were prominent in LCAD-/- mice. Progeny with the combined LCAD+/+//VLCAD+/- genotype were over-represented in offspring from sires and dams heterozygous for both LCAD and VLCAD mutations. In contrast, no live mice with a compound LCAD-/-//VLCAD-/- genotype were detected.

Original languageEnglish (US)
Pages (from-to)2069-2077
Number of pages9
JournalHuman molecular genetics
Volume10
Issue number19
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Cox, K. B., Hamm, D. A., Millington, D. S., Matern, D., Vockley, J., Rinaldo, P., Pinkert, C. A., Rhead, W. J., Lindsey, J. R., & Wood, P. A. (2001). Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse. Human molecular genetics, 10(19), 2069-2077. https://doi.org/10.1093/hmg/10.19.2069