Genomics of the human carnitine acyltransferase genes.

Five genes in the human genome are known to encode different active forms of related carnitine acyltransferases: CPT1A for liver-type carnitine palmitoyltransferase I, CPT1B for muscle-type carnitine palmitoyltransferase I, CPT2 for carnitine palmitoyltransferase II, CROT for carnitine octanoyltransferase, and CRAT for carnitine acetyltransferase. Only from two of these genes (CPT1B and CPT2) have full genomic structures been described. Data from the human genome sequencing efforts now reveal drafts of the genomic structure of CPT1A and CRAT, the latter not being known from any other mammal. Furthermore, cDNA sequences of human CROT were obtained recently, and database analysis revealed a completed bacterial artificial chromosome sequence that contains the entire CROT gene and several exons of the flanking genes P53TG and PGY3. The genomic location of CROT is at chromosome 7q21.1. There is a putative CPT1-like pseudogene in the carnitine/choline acyltransferase family at chromosome 19. Here we give a brief overview of the functional relations between the different carnitine acyltransferases and some of the common features of their genes. We will highlight the phylogenetics of the human carnitine acyltransferase genes in relation to the fungal genes YAT1 and CAT2, which encode cytosolic and mitochondrial/peroxisomal carnitine acetyltransferases, respectively.

Localization and intron usage analysis of the human CPT1B gene for muscle type carnitine palmitoyltransferase I.

We isolated and sequenced cDNA and genomic DNA fragments of the human CPT1B gene, encoding muscle type camitine palmitoyltransferase I. A recombinant P1 phage containing CPT1B was mapped to chromosome 22qter by fluorescent in situ hybridization. This finding supports the concept that 'liver type' and 'muscle type' isoforms of CPT I are encoded by different loci at separate chromosomal positions. Analysis of CPT1B cDNA sequences revealed the presence of an untranslated 5' exon and differential processing of introns 13 and 19. The alternative splicing of intron 13 causes an in-frame deletion leading to a 10 amino acid residues smaller protein. Using different splice acceptor sites, intron 19 is spliced in the majority of cases, but 4 out of 14 sequenced CPT1B 3' cDNA clones contain part of intron 19 in stead of exon 20. We found that differential polyadenylation is the mechanism behind the existence of these alternative 3' CPT1B mRNA forms.

Comparative circulatory effects of isoproterenol, dopamine, and dobutamine in conscious lambs with and without aortopulmonary left-to-right shunts.

We studied the effect on the circulation of the catecholamines isoproterenol, dopamine, and dobutamine in chronically instrumented lambs with aortopulmonary left-to-right shunts (ages 11 to 87 days) and without shunts (ages 8 to 97 days). Infusion of 0.1 microgram/kg/min isoproterenol or 10 micrograms/kg/min dobutamine markedly increased heart rate and systemic and pulmonary blood flows, while stroke volume and the left-to-right shunt flow did not change. Since pulmonary blood flow increased and the left-to-right shunt flow did not change, the left-to-right shunt fraction decreased with the infusions of isoproterenol and dobutamine. The hemodynamic changes during the infusion of isoproterenol and dobutamine occurred immediately after the start of infusion and stabilized within a few minutes. The pattern of hemodynamic changes was not influenced by the presence of an aortopulmonary left-to-right shunt or by age. Infusion of 10 micrograms/kg/min dopamine caused only small hemodynamic changes. This study shows that heart rate and systemic blood flow in the lamb are closely related. Furthermore, it demonstrates that despite an increased systemic blood flow, left-to-right shunt flow does not change after infusion of isoproterenol and dobutamine. Any decision as to which positive inotropic agent might be preferred at an early age should await experimental work concerning the effect of these agents on the myocardial oxygen demand and on the distribution of the systemic blood flow.