| *600528 | ||||||||||||||||||||||||||||||||||||||||||||||||
| CARNITINE PALMITOYLTRANSFERASE I, LIVER; CPT1A | ||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT IA CPT I, LIVER CPT1 | ||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: CPT1A | ||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 11q13.3 Genomic coordinates (GRCh37): 11:68,522,087 - 68,609,398 (from NCBI) | ||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||
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| TEXT | ||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||
| The CPT1A gene encodes carnitine palmitoyltransferase IA, a liver enzyme involved in fatty acid oxidation. The carnitine palmitoyltransferase (CPT; EC 2.3.1.21) enzyme system, in conjunction with acyl-CoA synthetase and carnitine/acylcarnitine translocase (613698), provides the mechanism whereby long-chain fatty acids are transferred from the cytosol to the mitochondrial matrix to undergo beta-oxidation for energy production. The CPT I isozymes (CPT1A and CPT1B; 601987) are located in the mitochondrial outer membrane and are detergent-labile, whereas CPT II (600650) is located in the inner mitochondrial membrane and is detergent-stable (Bieber, 1988; Murthy and Pande, 1987). | ||||||||||||||||||||||||||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||||||||||||||||||||||||||
| From a rat liver cDNA library, Esser et al. (1993) isolated a cDNA corresponding to carnitine palmitoyltransferase I. The deduced 773-amino acid protein has a molecular mass of 88 kD. A 4.7-kb mRNA was detected in rat liver. The authors suggested that the de novo synthesized enzyme is targeted to the mitochondrial outer membrane by a leader peptide, and that the mature protein anchors to the membrane through a 20-amino acid region near the N terminus. The findings established that CPT I and CPT II are distinct proteins and that inhibitors of CPT I interact within the catalytic domain, not with an associated regulatory component. Britton et al. (1995) used the cDNA for rat liver mitochondrial CPT I as a probe to isolate its counterpart from a human liver cDNA library. The predicted 773-amino acid protein shares 86% identity with the rat enzyme. Northern blot analysis detected a 4.7-kb mRNA in human liver. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Structure | ||||||||||||||||||||||||||||||||||||||||||||||||
| Gobin et al. (2002) used the working draft data of the human genome sequence to characterize the organization of the CPT1A gene. They showed the existence of 20 exons, spanning 60 kb of DNA. Two alternate promoters and numerous transcription factor-binding sites were identified within the 5-prime upstream region of the gene. In the 3-prime untranslated region, the major polyA signal was suggested to lie about 2 kb downstream of the stop codon. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||
| Britton et al. (1995) assigned the human liver CPT1 gene to 11q by testing of oligonucleotide primers specific to upstream and downstream regions of one of the exon-intron junctions in PCRs with DNA from a panel of somatic cell hybrids. One of the somatic cell hybrids that contained only a small portion of chromosome 11 (11q22-q23) gave negative results. By fluorescence in situ hybridization, Britton et al. (1997) mapped the CPT1A gene to chromosome 11q13.1-q13.5. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||||||||||||||||||||||||||
| Major control over fatty acid oxidation process is exerted at the level of CPT I by virtue of the unique inhibitability of this enzyme by malonyl-CoA. This fuel 'cross talk' was first recognized in the context of hepatic ketogenesis and its regulation and thereafter emerged as a central component of metabolism in a variety of tissues. For many years, it was unclear whether or not there were 2 distinct CPT proteins associated with mitochondrial beta-oxidation. Bergstrom and Reitz (1980) showed that CPT I and CPT II have similar physical characteristics, including molecular mass and kinetic properties, and that antibodies raised against each enzyme crossreacted with the other. Slama et al. (1996) demonstrated complementation between cells from CPT I- and CPT II-deficient (255110) individuals, indicating that the respective causative mutations of CPT I and CPT II deficiencies reside in distinct genes. Britton et al. (1997) established that liver and fibroblast express the same isoform of mitochondrial CPT1, legitimizing the use of fibroblast assays in the differential diagnosis of the 'muscle' (255110) and 'hepatic' (255120) forms of CPT deficiency. The findings established unequivocally that carnitine palmitoyltransferases I and II are distinct proteins encoded by separate genes. To investigate the mechanism by which central metabolism of lipids can modulate energy balance, Obici et al. (2003) selectively reduced lipid oxidation in the hypothalamus. The activity of CPT1 was decreased in rats either by administration of a ribozyme-containing plasmid designed specifically to decrease the expression of this enzyme, or by infusion of pharmacologic inhibitors of its activity into the third cerebral ventricle. Either genetic or biochemical inhibition of hypothalamic CPT1 activity was sufficient to diminish food intake and endogenous glucose production substantially. Obici et al. (2003) concluded that changes in the rate of lipid oxidation in selective hypothalamic neurons signaled nutrient availability to the hypothalamus, which in turn modulated the exogenous and endogenous inputs of nutrients into the circulation. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||
| In an infant with CPT IA deficiency (255120), IJlst et al. (1998) identified a homozygous mutation in the CPT1A gene (600528.0001). Yamamoto et al. (2000) reported 3 nonsense mutations, 1 missense mutation, and 2 splicing mutations in 4 Japanese patients with CPT IA deficiency. Ogawa et al. (2002) stated that 19 patients with CPT IA deficiency and 9 CPT1A mutations had been reported. Gobin et al. (2002) pointed out that while more than 200 families with CPT II deficiencies were known, fewer than 30 families with CPT IA deficiency had been reported prior to their report. Gobin et al. (2002) characterized 6 novel mutations in 4 CPT1A-deficient patients (600528.0003-600528.0008). | ||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, ASP454GLY [dbSNP:rs80356778] | ||||||||||||||||||||||||||||||||||||||||||||||||
| IJlst et al. (1998) described homozygosity for an asp454-to-gly (D454G) missense mutation of the CPT1A gene in a patient with CPT IA deficiency (255120), the offspring of consanguineous parents. She presented at 15 months of age with diarrhea and feeding difficulties. On admission, she was severely hypotonic and lethargic. Physical examination showed hepatomegaly and decreased tendon reflexes. Hypoketotic hypoglycemia was demonstrated. | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0002 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, GLU360GLY [dbSNP:rs80356787] | ||||||||||||||||||||||||||||||||||||||||||||||||
| In a Japanese patient with CPT IA deficiency (255120), Yamamoto et al. (2000) identified a 1079A-G mutation in the CPT1A gene, resulting in a glu360-to-gly (E360G) substitution. By functional expression studies in SV40 transformed fibroblasts, Ogawa et al. (2002) found that the E360G mutation caused decreased enzyme activity and protein levels, indicating that it is pathogenic. | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0003 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, GLN100TER [dbSNP:rs80356774] | ||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with CPT IA deficiency (255120), Gobin et al. (2002) identified a homozygous 298C-T substitution in exon 4 of the CPT1A gene, resulting in a gln100-to-ter (Q100X) mutation. The mutation truncated the protein by 671 amino acids. | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0004 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, ALA414VAL [dbSNP:rs80356790] | ||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with CPT IA deficiency (255120), Gobin et al. (2002) identified a 1241C-T substitution in exon 11 of the CPT1A gene, resulting in an ala414-to-val (A414V) mutation. Both the proband and the proband's father were heterozygous for the mutation. The same patient also had a 1493A-G substitution in exon 13 which produced a tyr498-to-cys (Y498C) mutation (600528.0005). Both the proband and the proband's mother were heterozygous for the mutation. Using functional and structural analysis, Gobin et al. (2003) found that the A414V mutation results in a severe decrease in protein expression (20- to 30-fold lower than wildtype), indicating protein instability, as well as a 98% decrease in catalytic activity of the CPT I enzyme. Modeling studies suggested that the mutation introduces a conformational change in the protein. | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0005 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, TYR498CYS [dbSNP:rs80356791] | ||||||||||||||||||||||||||||||||||||||||||||||||
| See 600528.0004 and Gobin et al. (2002). Using functional and structural analysis, Gobin et al. (2003) found that the Y498C mutation results in slight protein instability and a 3-fold decrease in enzyme activity. The affected residue is located at some distance from the active site of the enzyme and may cause indirect effects via a conformational change. | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0006 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, 153-BP DEL | ||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with CPT IA deficiency (255120), Gobin et al. (2002) identified a 153-bp deletion at nucleotide 1876 of the CPT1A gene resulting from a G-to-A substitution at the intron 15 splice acceptor site. The patient's mother was heterozygous for the mutation, which was not detected in the patient's father nor in 20 healthy controls. The mutation deleted 51 amino acids, from codons 626 to 676. The patient also had a 113-bp intronic insertion at nucleotide 1575 of the cDNA (600528.0007) resulting from retention of part of intron 13. | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0007 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, 113-BP INS | ||||||||||||||||||||||||||||||||||||||||||||||||
| See 600528.0006 and Gobin et al. (2002). | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0008 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, 8-KB DEL [dbSNP:rs80356797] | ||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with CPT IA deficiency (255120), Gobin et al. (2002) identified homozygosity for an 8-kb deletion in the CPT1A gene spanning the distal two-thirds of intron 14 to nucleotide 2107 in exon 17. The rearrangement deleted amino acids 581 to 702. | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0009 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, GLY709GLU [dbSNP:rs28936374] | ||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with CPT IA deficiency (255120) reported by Schaefer et al. (1997), Gobin et al. (2003) identified compound heterozygosity for 2 mutations in the CPT1A gene: a 2126G-A transition, resulting in a gly709-to-glu (G709E) substitution, and a 1-bp deletion (948delG), resulting in a premature termination signal in exon 10 (600528.0010). Using functional and structural analysis, Gobin et al. (2003) found that the G709E mutation resulted in significant protein instability and complete loss of enzyme function. The authors suggested that the mutation introduces a bulky and negatively charged group into the hydrophobic core of the enzyme, causing steric repulsions and unfavorable electrostatic interactions. | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0010 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, 1-BP DEL, 948G | ||||||||||||||||||||||||||||||||||||||||||||||||
| See 600528.0009 and Gobin et al. (2003). | ||||||||||||||||||||||||||||||||||||||||||||||||
| .0011 CARNITINE PALMITOYLTRANSFERASE IA DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||
| CPT1A, GLY710GLU [dbSNP:rs80356780] | ||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a large Hutterite kindred with CPT IA deficiency (255120), Prip-Buus et al. (2001) identified a homozygous 2129G-A transition in the CPT1A gene, resulting in a gly710-to-glu (G710E) substitution. Expression studies showed that the G710E mutation alters neither mitochondrial targeting nor stability of the protein, but kinetic studies showed that the mutant enzyme is completely catalytically inactive. The authors suspected a founder effect. | ||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||
| Zierz and Engel (1985) | ||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||
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