Alternative titles; symbols
HGNC Approved Gene Symbol: CPT2
Cytogenetic location: 1p32.3 Genomic coordinates (GRCh38) : 1:53,196,824-53,214,197 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p32.3 | {Encephalopathy, acute, infection-induced, 4, susceptibility to} | 614212 | Autosomal dominant; Autosomal recessive | 3 |
| CPT II deficiency, infantile | 600649 | Autosomal recessive | 3 | |
| CPT II deficiency, lethal neonatal | 608836 | Autosomal recessive | 3 | |
| CPT II deficiency, myopathic, stress-induced | 255110 | Autosomal dominant; Autosomal recessive | 3 |
The CPT2 gene encodes carnitine palmitoyltransferase II, an enzyme that participates 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. The CPT I isozymes (see CPT1A; 600528 and CPT1B; 601987) are located in the mitochondrial outer membrane and are detergent-labile, whereas CPT II is located in the inner mitochondrial membrane and is detergent-stable (Bieber, 1988).
By screening a human liver cDNA library, Finocchiaro et al. (1991) cloned and sequenced a cDNA encoding human carnitine palmitoyltransferase II. The deduced 658-amino acid protein contains a 25-residue NH2-terminal leader peptide. The amino acid sequence shows 82.2% homology with the rat CTP II protein.
Montermini et al. (1994) identified regulatory elements in the promoter of the CPT2 gene.
Verderio et al. (1995) determined that the CPT2 gene contains 5 exons spanning approximately 20 kb of DNA.
By human-hamster somatic cell hybridization, Finocchiaro et al. (1991) assigned the CPT2 gene (which they referred to as CPT1) to chromosome 1pter-q12. By fluorescence in situ hybridization, Minoletti et al. (1992) refined the assignment of the CPT2 gene to 1p13-p11. However, also using fluorescence in situ hybridization, Gellera et al. (1994) concluded that the CPT2 gene is located in band 1p32 and that the previously used probe that mapped the gene to 1p13-p11 'must be considered an as yet anonymous probe.' It is now clear that the gene mapped to chromosome 1p32 was CPT2.
Britton et al. (1995) distinguished CPT I and CPT II, and reported that major control over the fatty acid oxidation process is exerted at the level of CPT I by the unique inhibition of this enzyme by malonyl-CoA.
Slama et al. (1996) carried out complementation experiments between cell lines derived from patients with CPT I deficiency (255120) or infantile CPT II deficiency (600649) by measuring restoration of tritium release from palmitate. As expected, no complementation was observed in heteropolykaryons resulting from fusion of CPT I-deficient cells or of CPT II-deficient cells. Conversely, complementation was observed in fusions of CPT I- and CPT II-deficient cells. These data suggested that the defects in CPT I deficiency and infantile CPT II deficiency are determined by mutations in distinct genes. Palmitate oxidation by control or CPT I-deficient cell lines decreased when these cell lines were cocultured with infantile CPT II-deficient cell lines. This effect, not observed in a coculture with an adult CPT II-deficient cell line, was suppressed by a high carnitine concentration.
Finocchiaro et al. (1991), Minoletti et al. (1992), and Gellera et al. (1994) all referred to the CPT gene on chromosome 1 as CPT1; it is referred to here as CPT2 following the elucidation by Britton et al. (1995). CPT1 (600528) maps to chromosome 11.
Carnitine Palmitoyltransferase II Deficiency
In a patient with infantile carnitine palmitoyltransferase II deficiency (600649) with hypoketotic hypoglycemia and cardiomyopathy, Taroni et al. (1992) identified a homozygous mutation in the CPT2 gene (600650.0001). The patient was also homozygous for a mutant CPT2 allele (termed the 'ICV' allele) that carried 2 other rare polymorphisms. In a patient with infantile CPT II deficiency reported by Demaugre et al. (1991), Bonnefont et al. (1996) identified a homozygous mutation in the CPT2 gene (600650.0005).
In a Dutch patient with the myopathic form of CPT II deficiency (255110), Taroni et al. (1993) identified compound heterozygosity for 2 mutations in the CPT2 gene (600650.0001; 600650.0002).
Elpeleg et al. (2001) reported 2 Ashkenazi Jewish sibs with the antenatal, or lethal neonatal, form of CPT II deficiency (608836) who were homozygous for an allele carrying 2 mutations in exon 4 of the CPT2 gene (600650.0009).
Isackson et al. (2008) identified compound heterozygous or homozygous mutations in the CPT2 gene in 3 patients with lethal neonatal CPT II deficiency (see, e.g., 600650.0013) and in 2 patients with infantile CPT II deficiency. Three of the mutations were novel (see, e.g., 600650.0017).
Orngreen et al. (2005) identified 2 unrelated patients with mild features of late-onset (myopathic) CPT II deficiency who each carried a single mutation in the CPT2 gene (600650.0015 and 600650.0016). The findings indicated that some heterozygous CPT2 mutation carriers may be symptomatic.
Acute Infection-Induced Encephalopathy-4
Chen et al. (2005) found that a Japanese girl with fatal acute infection-induced encephalopathy-4 (IIAE4; 614212) was heterozygous for a thermolabile allele in the CPT2 gene (600650.0018). She had significantly increased serum acylcarnitine levels during febrile convulsions. Her 2 unaffected brothers, who were heterozygous for the allele, and their father, who was homozygous for the allele, had slightly increased serum acylcarnitine compared to normal values in the nonfebrile state. The mother, who was heterozygous only for the 368I, had normal acylcarnitine levels in the nonfebrile state.
In a study of 19 patients with CPT II deficiency, 13 with adult onset and 6 with infantile onset, Thuillier et al. (2003) found that all patients with the infantile form had mutations in exon 4 or 5 of the CPT2 gene. Twelve of the adult patients carried the S113L (600650.0002) mutation. Although there was an overlap in residual CPT II activity between the 2 groups (ranging from 4 to 12%), there was a significant decrease in palmitate oxidation in the infantile group (less than 10%) compared to the adult group (45 to 70%). Thuillier et al. (2003) concluded that both the type and location of CPT2 mutations and at least 1 additional, unidentified genetic factor modulate the long-chain fatty acid flux and therefore the severity of the disease.
In a patient with infantile carnitine palmitoyltransferase II deficiency (600649), Taroni et al. (1992) identified homozygosity for a mutant CPT2 allele (termed the 'ICV' allele) that carried 3 missense changes: a 1203G-A transition predicting a val368-to-ile substitution (V368I); a 1992C-T transition predicting an arg631-to-cys substitution (R631C); and a 2040A-G transition predicting a met647-to-val substitution (M647V). Screening of 59 healthy controls demonstrated that both the V368I and M647V mutations are sequence polymorphisms with allele frequencies of 0.5 and 0.25, respectively. The R631C substitution was not detected in 22 normal individuals or in 12 of 14 CPTase II-deficient patients with the muscular (myopathic) form of CPT II deficiency (255110). Notably, 2 of the adult CPTase II-deficient patients were heterozygous for the triply mutant ICV allele, suggesting compound heterozygosity for this and a different mutant allele. In vitro functional expression studies showed that the R631C substitution drastically depressed catalytic activity of the CPT II protein. The V368I and M647V mutations, although not affecting enzyme activity alone, exacerbated the effects of the R631C substitution.
In a Dutch patient with adult-onset (myopathic) CPT II deficiency, Taroni et al. (1993) identified compound heterozygosity for the R631C mutation and the S113L mutation (600650.0002). Another unrelated Italian patient with the myopathic form had the R631C mutation on 1 allele.
In 8 unrelated patients with familial recurrent myoglobinuria due to carnitine palmitoyltransferase II deficiency (255110), Taroni et al. (1993) identified a homozygous 439C-T transition in the CPT2 gene, resulting in a ser133-to-leu substitution (S133L). One of the patients had been reported by DiDonato et al. (1978). Among a total of 25 patients with the disorder, Taroni et al. (1993) found the S113L mutation in 56% of the mutant CPT II alleles and concluded that the S113L missense mutation is the most frequent change found in the myopathic form of CPT II deficiency. One Dutch patient was compound heterozygous for the S113L mutation and the R631C (600650.0001) mutation. In vitro functional expression studies showed that the S113L mutation resulted in normal protein synthesis, but a markedly reduced steady-state level, indicating decreased stability of the mutant protein.
By in vitro functional analysis in fibroblasts, Bonnefont et al. (1996) showed that the S113L mutation resulted in 20% CPT II residual activity with no consequence on long-chain fatty acid (LCFA) oxidation, whereas the Y628S mutation (600650.0005), found in the more severe infantile form of the disorder (600649), resulted in 10% CPT II residual activity and markedly impaired LCFA oxidation. Bonnefont et al. (1996) concluded that CPT II activity must be reduced below a critical threshold for LCFA oxidation in fibroblasts to be impaired. This critical threshold differs among tissues, thus providing a basis for the phenotypic heterogeneity of CPT II deficiency.
In 3 related patients with CPT II deficiency from consanguineous marriages, 2 sibs and a first cousin, Handig et al. (1996) identified homozygosity for the S113L mutation. The cases could be traced back to a common ancestral couple 5 generations earlier. The family showed clinical variability of the disorder.
Martin et al. (1999) identified the S113L mutation in 8 of 14 Spanish patients from 10 unrelated families. Seven patients were homozygous for the mutation, 1 patient was heterozygous, and 6 patients did not carry the mutation on either allele. The mutation was found in the heterozygous state in 7 healthy relatives belonging to 3 different families.
Joshi et al. (2012) reported 2 unrelated patients with stress-induced myopathic carnitine palmitoyltransferase II deficiency who were heterozygous for the S113L mutation. One patient, a 21-year-old female professional tennis player, suffered from exercise-induced attacks of muscle pain, burning sensations, and proximal weakness. The other patient, a 30-year-old male amateur marathon runner, developed muscle cramps and rhabdomyolysis upon extensive exercise and insolation-induced fever.
In patients with the myopathic form of CPT II deficiency (255110), Verderio et al. (1995) identified a 665C-A transversion in exon 1 of the CPT2 gene, resulting in a pro50-to-his (P50H) substitution. This amino acid substitution occurred within a leucine-proline motif that is highly conserved in acyltransferases from different species. The mutation was detected in both alleles of a patient of Italian ancestry and in 1 allele of 1 patient each of Italian, Dutch, and French ancestry.
Vladutiu et al. (2002) reported a male infant of mixed heritage with the late infantile form of CPT II (600649) who was compound heterozygous for the P50H mutation and for a truncating 2-bp deletion (see 600650.0009). He presented at age 11 months with hypoglycemia, vomiting, and lethargy after a febrile illness. Dietary management was successful, and he was normal appearing at age 5 years. CPT II activity in fibroblasts was 17% of normal. Vladutiu et al. (2002) noted that the P50H mutation is usually associated with late-onset disease and postulated that compound heterozygosity for a mild and a severe CPT2 mutation causes an intermediate phenotype.
In a patient of Italian ancestry with the myopathic form of CPT II deficiency (255110), Verderio et al. (1995) identified compound heterozygosity for 2 mutations in the CPT2 gene: a 2173G-A transition in exon 5, resulting in an asp553-to-asn (D553N) substitution, and S113L (600650.0002). Immunoblot analysis demonstrated that both mutations were associated with a markedly reduced steady-state level of the protein, indicating decreased stability of the mutant gene product.
In an infant with the infantile form of CPT II deficiency (600649) originally reported by Demaugre et al. (1991), Bonnefont et al. (1996) identified a homozygous 2399A-C transversion in the CPT2 gene, resulting in a tyr628-to-ser (Y628S) substitution. In vitro functional analysis in fibroblasts showed that the Y628S mutation resulted in 10% CPT II residual activity and markedly impaired oxidation of long-chain fatty acids, whereas the S113L (600650.0002) mutation found in the less severe myopathic form of the disorder (255110) resulted in 20% CPT II residual activity, without consequence on LCFA oxidation. Bonnefont et al. (1996) concluded that CPT II activity must be reduced below a critical threshold for LCFA oxidation in fibroblasts to be impaired. This critical threshold differs among tissues, thus providing a basis for the phenotypic heterogeneity of CPT II deficiency.
Martin et al. (1999) reported a patient with the myopathic form of CPT II deficiency who had the Y628S mutation on 1 allele.
In 2 Japanese sibs with the infantile form of CPT II deficiency (600649), Yamamoto et al. (1996) identified compound heterozygosity for 2 mutations in the CPT2 gene: a 621G-A transition resulting in a glu174-to-lys (E174K) substitution, and a 1249T-A transversion resulting in a phe383-to-tyr (F383Y; 600650.0007) substitution.
For discussion of the phe383-to-tyr (F838Y) mutation in the CPT2 gene that was found in compound heterozygous state in 2 Japanese patients with infantile CPT II deficiency (600649) by Yamamoto et al. (1996), see 600650.0006.
Aoki et al. (2007) reported a 21-year-old Japanese woman with the myopathic form of CPT II deficiency (255110) associated with a homozygous F383Y mutation. At age 19 and again at age 21, she had episodes of myalgia, dark urine, and increased serum creatine kinase during viral illnesses. Residual CPT2 activity ranged from 2 to 7% of normal controls, which the authors noted was usually associated with the more severe form of the disorder. Family history revealed a brother and sister who both died as infants.
Vladutiu et al. (1998, 2000) reported a family in which a woman, her father, and her son were heterozygous for an arg503-to-cys (R503C) mutation in a highly conserved region of the CPT2 gene. Sequence analysis showed no other change in CPT2. The 54-year-old mother had a 35-year history of progressive muscle weakness and myopathic symptoms associated with reduced CPT II activity (255110) in lymphoblasts (47% of normal), fibroblasts (43%), and skeletal muscle (13%). Her 26-year-old son had a lifelong history of myopathic symptoms, whereas his grandfather had only mild weakness during childhood. The son had survived an episode of malignant hyperthermia during surgery at 4 years of age, during which CPK went to values greater than 5,000 mU/mL. Analysis of the V368I and M647V polymorphisms (see 600650.0001) in the CPT2 gene showed that the mutant allele was linked to 368I and 647M in this family, and that the normal allele was linked to 647V in the affected patient and her son and to 647M in the patient's father. In common with malignant hyperthermia-associated mutations affecting skeletal muscle in the RYR1 (180901) and CACNL1A3 (114208) genes, the clinical, biochemical, and genetic evidence in this family suggested that the R503C substitution in CPT2 may cause a latent myopathy that becomes apparent only after specific anesthetic exposure.
Taggart et al. (1999) reported 4 Ashkenazi Jewish patients with late-onset CPT II deficiency (255110) who were compound heterozygous for a CPT2 allele with a 2-bp deletion, which they termed 413delAG, and a phe448-to-leu (F448L) substitution, and for the S113L (600650.0002) mutation. The 2-bp deletion causes a premature termination codon at residue 420; thus, the F448L change is not contained within the truncated protein and does not have functional significance.
Elpeleg et al. (2001) reported 2 Ashkenazi Jewish sibs with the antenatal form of CPT II deficiency (608836) who were homozygous for the allele carrying the 2 mutations in exon 4 of the CPT2 gene; the 1-bp deletion, which they termed 1237delAG, and the F448L mutation. Both sibs had periventricular calcifications and markedly enlarged kidneys found in the fifth gestational month. Activity of CPT II in lymphocytes was undetectable. The 1237delAG mutation was predicted to result in a truncated protein at 65% of its normal length. Referring to the findings of Taggart et al. (1999), Elpeleg et al. (2001) suggested that this allele is common in the Ashkenazi Jewish population.
Vladutiu et al. (2002) reported a male infant of mixed heritage with the late infantile form of CPT II (600649) and episodic hypoglycemia who was compound heterozygous for the 2-bp deletion and the P50H (600650.0003) mutation. A male infant of Ashkenazi Jewish descent with the lethal neonatal form of CPT II was compound heterozygous for the 2-bp deletion and a 3-bp deletion/5-bp insertion (600650.0014).
In a Moroccan family in which 4 sibs died from neonatal CPT II deficiency (608836), Smeets et al. (2003) identified a novel splice site mutation in the CPT2 gene: a G-to-A transition in the splice acceptor site of intron 2 (IVS2-1G-A; 600650.0011). Studies at the mRNA level indicated that the affected children were homozygous for an insertion of a threonine at codon 534 (534insT) followed by a 25-bp deletion (bases 534-558). Studies of genomic DNA, however, revealed all patients were compound heterozygous for this 534insT/del25 mutation, and, on the other allele, for the novel splice site mutation. The findings underscored the incompleteness of mutation detection at the mRNA level in cases where a mutation leads to aberrant splicing or nonsense-mediated messenger decay.
For discussion of the splice site mutation (IVS2-1G-A) in the CPT2 gene that was found in compound heterozygous state in sibs with neonatal CPT II deficiency (608836) by Smeets et al. (2003), see 600650.0010.
In 2 sibs with lethal neonatal CPT II deficiency (608836) originally reported by Witt et al. (1991), Gellera et al. (1992) identified a heterozygous 11-bp insertion mutation in exon 4 of the CPT2 gene (nucleotides 997-1007). The insertion results in a premature termination signal predicted to truncated the CPT2 protein by approximately 350 amino acids at the C terminus. The unaffected mother carried the insertion mutation, but the father had only wildtype alleles; Gellera et al. (1992) concluded that an additional, unidentified CPT2 mutation was present in the affected sibs. Cultured fibroblasts from the patients showed a 92% reduction in CPT II activity and virtual absence of the protein, indicating that complete CPT2 deficiency is a lethal condition.
In a premature Haitian infant with neonatal lethal CPT II deficiency (608836), Taroni et al. (1994) identified a homozygous mutation in exon 4 of the CPT2 gene, resulting in a pro227-to-leu (P227L) substitution. No CPT2 protein was detected by Western blot analysis of fibroblasts, and in vitro analysis demonstrated normal amounts of newly synthesized CPT II, suggesting decreased enzyme stability. CPT II residual activity was measured at less than 15% of normal control values. The parents were heterozygous for the mutation.
Isackson et al. (2008) identified a homozygous P227L mutation in an African American patient with lethal neonatal CPT II deficiency. The infant appeared normal at birth but developed hypoglycemia in the nursery. She also had heart block, polycystic kidneys, and seizures, and died at age 14 days. Laboratory studies showed significantly increased plasma carnitine species. Isackson et al. (2008) noted that the P227L substitution is located at the C-terminal end of the beta-2 strand. The authors postulated that the mutation affects enzyme stability, since the affected residue is not near the active site.
In a male infant of Ashkenazi Jewish descent with the lethal neonatal form of CPT II (608836) first reported by Albers et al. (2001), Vladutiu et al. (2002) identified compound heterozygosity for a 2-bp deletion (see 600650.0009) and a 109AGC-GCAGC change (3-bp deletion and 5-bp insertion) in the CPT2 gene. The infant died on the third day of life; CPT II activity was 6% and 18% of normal in fibroblasts and skeletal muscle, respectively.
Orngreen et al. (2005) identified a heterozygous glu454-to-ter (E454X) mutation in the CPT2 gene in a man who had experienced an episode of rhabdomyolysis after ingestion of alcohol and no food the night before a swimming practice. Residual CPT2 enzyme activity was 46% of normal control values, and biochemical studies indicated impaired fatty acid oxidation with prolonged exercise, which is consistent with stress-induced myopathic CPT II deficiency (255110). Orngreen et al. (2005) suggested that the E454X truncated CPT2 protein may be incorporated into the tetrameric structure of the enzyme complex, resulting in a dominant-negative effect, and that some heterozygous carriers of CPT2 mutations may be symptomatic.
Orngreen et al. (2005) identified a heterozygous asp213-to-gly (D213G) mutation in the CPT2 gene in a woman with exercise intolerance and muscle cramps. Residual CPT2 enzyme activity was 65% of normal control values, and biochemical studies indicated impaired fatty acid oxidation with prolonged exercise, which is consistent with stress-induced myopathic CPT II deficiency (255110). The D213G substitution occurs in a highly conserved domain of the protein, and the authors suggested that the change may compromise normal enzyme function. The woman had 2 children with myopathic CPT II deficiency caused by compound heterozygous mutations in the CPT2 gene: D213G and S113L (600650.0002). The asymptomatic father was heterozygous for the S113L mutation. Orngreen et al. (2005) suggested that some heterozygous carriers of CPT2 mutations may be symptomatic.
In a patient with infantile CPT II deficiency (600649), Isackson et al. (2008) identified a homozygous 359A-G transition in the CPT2 gene, resulting in a tyr120-to-cys (Y120C) substitution. The location of the mutation was predicted to interfere with the active site. CPT2 activity was 2.5% of control values. The patient presented at age 15 months following a febrile episode with hypoglycemic encephalopathy and hepatomegaly. There was complete neurologic recovery, and the patient did well with proper treatment.
Chen et al. (2005) found an association between 2 thermolabile polymorphisms in the CPT2 gene and susceptibility to infection-induced acute encephalopathy-4 (IIAE4; 614212) in Japanese children. The variants were a 1055T-G transversion, resulting in a phe352-to-cys (F352C) substitution (rs2229291), and a 1102G-A transition, resulting in a val368-to-ile (V368I) substitution (rs1799821). Four (30.8%) of 13 patients with the disorder carried these alleles, compared to 6 (7.6%) of 79 controls (p less than 0.025). In vitro functional studies in COS-7 cells showed that the 352C/368I allele had significantly reduced activity (34.7% compared to wildtype) at 37 degrees C, and was decreased even more at 41 degrees C (less than 30% of wildtype at 37 degrees). The 352C/368V allele showed less severely decreased activity (62.8% of wildtype) at 37 degrees C, with again a further decrease at 41 degrees C. Chen et al. (2005) noted that the allelic frequency of F352C in Japan is 0.21, and that this variant has not been reported in Caucasians. The allelic frequency of V368I is 0.70 in Japan and 0.51 in southern European populations. Viral-associated encephalopathy is characterized by a high-grade fever accompanied within 12 to 48 hours by febrile convulsions, often leading to coma, multiple-organ failure, and high morbidity and mortality. Chen et al. (2005) concluded that their findings suggest that a continuous high-grade fever, often accompanied by fasting, causes a systemic and metabolic energy crisis in patients with thermolabile polymorphic variations in the CPT2 gene.
In vitro studies by Yao et al. (2008) demonstrated that the F352C/V368I variant proteins exerted a dominant-negative effect on the CPT2 homotetramer and had shortened half-lives compared to wildtype, consistent with intracellular instability. The studies also confirmed thermolability, with attenuated CPT2 activity associated with decreased ATP levels at higher temperatures. Yao et al. (2008) hypothesized that ATP depletion may cause increased blood-brain barrier permeability and contribute to cerebral edema in affected individuals.
Among 29 Japanese patients with infection-induced acute encephalopathy, Shinohara et al. (2011) found significantly higher frequency of the 352C variant in exon 4 of the CPT2 gene compared to controls (27.6 vs 13.5%, odds ratio of 2.44, p = 0.011). All patients with 352C had the 368I allele and the 647M allele (CIM haplotype). There was no difference in allele frequency between patients with a clinical diagnosis of acute necrotizing encephalopathy and those with acute encephalopathy with biphasic seizures and late reduced diffusion, and there was no correlation between good and poor prognosis.
Mak et al. (2011) reported 2 unrelated Chinese boys from Hong Kong with fatal virally-induced acute encephalopathy. Both were heterozygous for F352C and homozygous for V368I. The infectious agents were Coxsackie virus group A in 1 patient and influenza A, subtype H1 in the other. Both patients had high fever, seizures, and rapid deterioration with cerebral edema and multiorgan failure. Plasma acylcarnitines were increased in all mutation carriers, including asymptomatic parents.
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