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Research Article Free access | 10.1172/JCI2927

Molecular basis of hepatic carnitine palmitoyltransferase I deficiency.

L IJlst, H Mandel, W Oostheim, J P Ruiter, A Gutman, and R J Wanders

Department of Clinical Chemistry, University of Amsterdam, Academic Medical Center, 1100 DE Amsterdam, The Netherlands.

Find articles by IJlst, L. in: JCI | PubMed | Google Scholar

Department of Clinical Chemistry, University of Amsterdam, Academic Medical Center, 1100 DE Amsterdam, The Netherlands.

Find articles by Mandel, H. in: JCI | PubMed | Google Scholar

Department of Clinical Chemistry, University of Amsterdam, Academic Medical Center, 1100 DE Amsterdam, The Netherlands.

Find articles by Oostheim, W. in: JCI | PubMed | Google Scholar

Department of Clinical Chemistry, University of Amsterdam, Academic Medical Center, 1100 DE Amsterdam, The Netherlands.

Find articles by Ruiter, J. in: JCI | PubMed | Google Scholar

Department of Clinical Chemistry, University of Amsterdam, Academic Medical Center, 1100 DE Amsterdam, The Netherlands.

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Department of Clinical Chemistry, University of Amsterdam, Academic Medical Center, 1100 DE Amsterdam, The Netherlands.

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Published August 1, 1998 - More info

Published in Volume 102, Issue 3 on August 1, 1998
J Clin Invest. 1998;102(3):527–531. https://doi.org/10.1172/JCI2927.
© 1998 The American Society for Clinical Investigation
Published August 1, 1998 - Version history
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Abstract

Mitochondrial fatty acid beta-oxidation is important for energy production, which is stressed by the different defects found in this pathway. Most of the enzyme deficiencies causing these defects are well characterized at both the protein and genomic levels. One exception is carnitine palmitoyltransferase I (CPT I) deficiency, of which until now no mutations have been reported although the defect is enzymatically well characterized. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Here we report the first delineation of the molecular basis of hepatic CPT I deficiency in a new case. cDNA analysis revealed that this patient was homozygous for a missense mutation (D454G). The effect of the identified mutation was investigated by heterologous expression in yeast. The expressed mutant CPT IA displayed only 2% of the activity of the expressed wild-type CPT IA, indicating that the D454G mutation is the disease-causing mutation. Furthermore, in patient's fibroblasts the CPT IA protein was markedly reduced on immunoblot, suggesting that the mutation renders the protein unstable.

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