MOLECULAR ANALYSIS OF CARNITINE PALMITOYLTRANSFERASE-II DEFICIENCY WITH HEPATOCARDIOMUSCULAR EXPRESSION

Carnitine palmitoyltransferase (CPT) II deficiency, an inherited disor der of mitochondrial long-chain fatty-acid (LCFA) oxidation, results i n two distinct clinical phenotypes, namely, an adult (muscular) form a nd an infantile (hepatocardiomuscular) form. The rationale of this phe notypic heterogeneity is poorly understood. The adult form of the dise ase is commonly ascribed to the Ser-113-Leu substitution in CPT II. On ly few data are available regarding the molecular basis of the infanti le form of the disease. We report herein a homozygous A-2399-C transve rsion predicting a Tyr-628-Ser substitution in a CPT II-deficient infa nt. In vitro expression of mutant cDNA in COS-1 cells demonstrated the responsibility of this mutation for the disease. Metabolic consequenc es of the Ser-113-Leu and Tyr-628-Ser substitutions were studied in fi broblasts. The Tyr-628-Ser substitution (infantile form) resulted in a 10% CPT II residual activity, markedly impairing LCFA oxidation, wher eas the Ser-113-Leu substitution (adult form) resulted in a 20% CPT II residual activity, without consequence on LCFA oxidation. These data show that CPT II activity has to be reduced below a critical threshold in order for LCFA oxidation in fibroblasts to be impaired. The hypoth esis that this critical threshold differs among tissues could provide a basis to explain phenotypic heterogeneity of CPT II deficiency.