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Hum Mol Genet. 1995 Jan;4(1):19-29.

Carnitine palmitoyltransferase II deficiency: structure of the gene and characterization of two novel disease-causing mutations.

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  • 1Divisione di Biochimica e Genetica, Istituto Nazionale Neurologico Carlo Besta, Milan, Italy.


Carnitine palmitoyltransferase (CPT) II deficiency is the most common inherited disorder of lipid metabolism affecting skeletal muscle. To facilitate the identification of disease-causing mutations in the CPT II gene (CPT1), we have established the genomic organization of this gene. CPT1 spans approximately 20 kb of 1p32 and is composed of five exons ranging from 81 to 1305 bp. The sequences of the exon--intron boundaries were determined for each exon and conformed to the consensus splice junction sequences. The 5' and 3' untranslated regions in exon 1 and 5, respectively, were also determined, including the polyadenylation signal and the polyadenylation site. The mature transcript is predicted to be 3090 nt in length. CPT1 exons from CPT II-deficient patients were amplified and directly sequenced. Two novel disease-causing mutations were identified and characterized. The first mutation was a C-665-to-A transversion in exon 1 resulting in a proline-to-histidine substitution at residue 50 of the protein (P50H). This amino acid substitution occurs within a leucine-proline motif that is highly conserved in acyltransferases from different species. The mutation was detected in both alleles of patient 05SB of Italian ancestry, and in one allele of patients 11EG, 38PG, and 26FD of Italian, Dutch, and French ancestry, respectively. The second mutation was a rare G-2173-to-A transition in exon 5 causing an aspartic-acid-to-asparagine substitution at amino acid 553 (D553N) and the generation of a new MseI site. The mutation was detected only in one allele of patient 15MB, of Italian ancestry, who was also heterozygous for the common S113L substitution. Transfection experiments in COS cells demonstrated that both mutations drastically depressed the catalytic activity of CPT II. Biochemical characterization of P50H mutant CPT II in cultured cells from patient 05SB showed that the mutation does not affect substrate binding sites. Finally, immunoblot analysis demonstrated that both mutations were associated with markedly reduced steady-state level of the protein, thus indicating decreased stability of the mutant CPT II.

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