HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brown, N. F. Articles by Cohen, J. C. Search for Related Content PubMed PubMed Citation Articles by Brown, N. F. Articles by Cohen, J. C. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 42, 1134-1142, July 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme

Correspondence to: Jonathan C. Cohen, at the Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9052., jonathan.cohen{at}utsouthwestern.edu (E-mail)

Carnitine palmitoyltransferase I (CPT I) catalyzes the formation of acylcarnitine, the first step in the oxidation of long-chain fatty acids in mitochondria. The enzyme exists as liver (L-CPT I) and muscle (M-CPT I) isoforms that are encoded by separate genes. Genetic deficiency of L-CPT I, which has been reported in 16 patients from 13 families, is characterized by episodes of hypoketotic hypoglycemia beginning in early childhood and is usually associated with fasting or illness. To date, only two mutations associated with L-CPT I deficiency have been reported. In the present study we have identified and characterized the mutations underlying L-CPT I deficiency in six patients: five with classic symptoms of L-CPT I deficiency and one with symptoms that have not previously been associated with this disorder (muscle cramps and pain). Transfection of the mutant L-CPT I cDNAs in COS cells resulted in L-CPT I mRNA levels that were comparable to those expressed from the wild-type construct. Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability. The patient with atypical symptoms had 20% of normal L-CPT I activity and was homozygous for a mutation (c.1436CT) that substituted leucine for proline at codon 479. Assays performed with his cultured skin fibroblasts indicated that this mutation confers partial resistance to the inhibitory effects of malonyl-CoA.

The demonstration of L-CPT I deficiency in this patient suggests that the spectrum of clinical sequelae associated with loss or alteration of L-CPT I function may be broader than was previously recognized. — Brown, N. F., R. S. Mullur, I. Subramanian, V. Esser, M. J. Bennett, J-M. Saudubray, A. S. Feigenbaum, J. A. Kobari, P. M. Macleod, J. D. McGarry, and J. C. Cohen. Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme. J. Lipid Res. 2001. 42: 1134;–1142.

Supplementary key words: hypoketotic hypoglycemia, acylcarnitine, fatty acid oxidation, fasting, malonyl-CoA

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Rajakumar, M. R. Ban, H. Cao, T. K. Young, P. Bjerregaard, and R. A. Hegele Carnitine palmitoyltransferase IA polymorphism P479L is common in Greenland Inuit and is associated with elevated plasma apolipoprotein A-I J. Lipid Res., June 1, 2009; 50(6): 1223 - 1228. [Abstract] [Full Text] [PDF]

				S. B. Narayan, R. L. Boriack, B. Messmer, and M. J. Bennett Establishing a Reference Interval For Measurement of Flux through the Mitochondrial Fatty Acid Oxidation Pathway in Cultured Skin Fibroblasts Clin. Chem., March 1, 2005; 51(3): 644 - 646. [Full Text] [PDF]

				H. Liu, G. Zheng, M. Treber, J. Dai, and G. Woldegiorgis Cysteine-scanning Mutagenesis of Muscle Carnitine Palmitoyltransferase I Reveals a Single Cysteine Residue (Cys-305) Is Important for Catalysis J. Biol. Chem., February 11, 2005; 280(6): 4524 - 4531. [Abstract] [Full Text] [PDF]

				S. Gobin, L. Thuillier, G. Jogl, A. Faye, L. Tong, M. Chi, J.-P. Bonnefont, J. Girard, and C. Prip-Buus Functional and Structural Basis of Carnitine Palmitoyltransferase 1A Deficiency J. Biol. Chem., December 12, 2003; 278(50): 50428 - 50434. [Abstract] [Full Text] [PDF]

				J. Marin-Garcia and M. J. Goldenthal Fatty acid metabolism in cardiac failure: biochemical, genetic and cellular analysis Cardiovasc Res, June 1, 2002; 54(3): 516 - 527. [Full Text] [PDF]

				M. Morillas, P. Gomez-Puertas, B. Rubi, J. Clotet, J. Arino, A. Valencia, F. G. Hegardt, D. Serra, and G. Asins Structural Model of a Malonyl-CoA-binding Site of Carnitine Octanoyltransferase and Carnitine Palmitoyltransferase I. MUTATIONAL ANALYSIS OF A MALONYL-CoA AFFINITY DOMAIN J. Biol. Chem., March 22, 2002; 277(13): 11473 - 11480. [Abstract] [Full Text] [PDF]

				M. Morillas, P. Gomez-Puertas, R. Roca, D. Serra, G. Asins, A. Valencia, and F. G. Hegardt Structural Model of the Catalytic Core of Carnitine Palmitoyltransferase I and Carnitine Octanoyltransferase (COT). MUTATION OF CPT I HISTIDINE 473 AND ALANINE 381 AND COT ALANINE 238 IMPAIRS THE CATALYTIC ACTIVITY J. Biol. Chem., November 21, 2001; 276(48): 45001 - 45008. [Abstract] [Full Text] [PDF]