TY - JOUR
T1 - Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse
AU - Cox, Keith B.
AU - Hamm, Doug A.
AU - Millington, David S.
AU - Matern, Dietrich
AU - Vockley, Jerry
AU - Rinaldo, Piero
AU - Pinkert, Carl A.
AU - Rhead, William J.
AU - Lindsey, J. Russell
AU - Wood, Philip A.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/10.19.2069
DO - 10.1093/hmg/10.19.2069
M3 - Article
C2 - 11590124
AN - SCOPUS:0034782503
SN - 0964-6906
VL - 10
SP - 2069
EP - 2077
JO - Human molecular genetics
JF - Human molecular genetics
IS - 19
ER -