Alternative titles; symbols
HGNC Approved Gene Symbol: SLC25A20
SNOMEDCT: 238003000;
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:48,856,926-48,898,882 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Carnitine-acylcarnitine translocase deficiency | 212138 | Autosomal recessive | 3 |
The SLC25A20 gene encodes carnitine-acylcarnitine translocase (CACT), one of the components of the carnitine cycle. The carnitine cycle is necessary to shuttle long-chain fatty acids from the cytosol into the intramitochondrial space where mitochondrial beta-oxidation of fatty acids takes place (summary by Rubio-Gozalbo et al., 2004).
Huizing et al. (1997) cloned and sequenced the human CACT cDNA, which has an open reading frame of 903 bp. They symbolized the gene CAC, for carnitine-acylcarnitine carrier. Northern blot studies showed different expression levels of the gene in various human tissues. Huizing et al. (1998) studied the human tissue distribution of mitochondrial transmembrane metabolite carriers by Northern and Western blot analyses. They found a high level of CACT mRNA transcripts in heart, skeletal muscle, and liver, and much lower levels in brain, placenta, kidney, pancreas, and especially in lung.
Iacobazzi et al. (1998) determined that the CACT protein contains 6 transmembrane segments and has cytoplasmic N- and C-termini. CACT also has 3 large extracellular loops between transmembrane segments 1 and 2, 3 and 4, and 5 and 6.
Iacobazzi et al. (1998) determined that the SLC25A20 gene contains 9 coding exons and spans 16.5 kb. Exon 1 is GC-rich, and intron 1 contains a long interspersed sequence.
By fluorescence in situ hybridization, Viggiano et al. (1997) mapped the CACT gene to 3p21.31 and its pseudogene, CACTP, to 6p12.
Tachibana et al. (2005) showed that the expression of SLC25A20 was upregulated by PPAR-alpha (PPARA; 170998), a ligand-activated transcription factor with a central role in the control of lipid metabolism. Tachibana et al. (2009) confirmed that SLC25A20 mRNA and protein was positively upregulated by ligand-activated PPAR-alpha in human hepatoblastoma cell lines. Sequence analysis, reporter gene assays, electrophoretic mobility shift assays, and supershift assays confirmed the functional binding of PPAR-alpha to a peroxisome proliferator responsive element (PPRE) in the promoter region of the SLC25A20 gene.
By direct sequencing of CACT (SLC25A20) cDNA from an infant with carnitine-acylcarnitine translocase deficiency (CACTD; 212138), Huizing et al. (1997) identified a homozygous cytosine insertion (613698.0001). The insertion caused a frameshift and an extension of the open reading frame with 23 novel codons.
In a child with CACT deficiency who was the product of a consanguineous marriage, Iacobazzi et al. (2004) identified homozygosity for a gln238-to-arg mutation in the SLC25A20 gene (Q238R; 613698.0007). Both parents were heterozygous for the mutation.
Iacobazzi et al. (2004) found significant clinical heterogeneity among 6 CACT-deficient patients from Italy, Spain, and North America. In 5 patients, the disease manifested in the neonatal period, whereas the remaining patient, the younger sib of an infant who had died with clinical suspicion of fatty acid oxidation defect, had been treated since birth and was clinically asymptomatic at 4.5 years of age. Sequence analysis of the SLC25A20 gene identified 5 novel mutations and 3 previously reported mutations. Combined analysis of clinical, biochemical, and molecular data failed to indicate a correlation between phenotype and genotype.
In 2 unrelated Japanese infants with CACTD, Fukushima et al. (2013) identified compound heterozygous mutations in the CACT gene (613698.0006, 613698.0008-613698.0009).
Huizing et al. (1997) identified homozygosity for a 1-bp insertion in the CACT gene in a 9-year-old girl with carnitine-acylcarnitine translocase deficiency (CACTD; 212138). She had survived a severe neonatal condition consisting of hypoglycemia, cardiac arrest, hepatomegaly, and hepatic dysfunction--all features often observed in patients with a fatty-acid oxidation disorder. Episodes of lethargy and hepatomegaly occurred thereafter during mild viral infections. Later physical and neurophysiologic development was essentially normal. The girl did well with prolonged exercise, and between attacks she was alert, cooperative, and pleasant. Sequencing of the patient's cDNA for CACT showed insertion of a cytosine in a cytosine-rich region. The protein encoded by the CACT gene is 301 amino acids long; the insertion changed the sequence of the CACT protein from amino acid 300 (asparagine to glutamine) to the C terminus and expanded the length of the protein by 21 amino acids, to a total of 322 amino acids.
In 2 sibs with carnitine-acylcarnitine translocase deficiency (CACTD; 212138), the offspring of consanguineous Turkish parents, Huizing et al. (1998) identified compound heterozygosity for 2 deletions of the CACT gene: deletion of 128 bp (basepairs 261-388) and deletion of 110 bp (basepairs 671-780) (613698.0003). In each case a premature stop codon was introduced owing to frameshift. Further studies indicated that no product carrying both deletions was obtained, suggesting that the patient was a compound heterozygote (despite consanguinity of the parents). It was predicted that the number of amino acids, 301 in the wildtype protein, was reduced to 139 in the first deletion and 211 in the second deletion. The patient in this case became somnolent, had bradycardia, and developed generalized skeletal muscle weakness by the third day of life. Hypoglycemia, moderate metabolic acidosis, increased plasma ammonia concentrations, and dicarboxylic aciduria were found. During an attack of cardiac arrhythmias and arrest he was resuscitated and artificial ventilation was started, which was continued until death at the age of 8 weeks. On treatment he developed hypertrophic cardiomyopathy and marked hepatomegaly. At least one other child in this sibship, a girl, was well until the sixth day of life when she developed a course of disease strikingly similar to that of her younger brother, with somnolence, tachyarrhythmias, and cardiorespiratory distress requiring resuscitation. Later she showed mild hyperammonemia, hepatomegaly with abnormal liver functions and seizures, and she died with multiorgan failure at the age of 5 weeks.
For discussion of the 110-bp deletion (basepairs 671-680) in the SLC25A20 gene that was found in compound heterozygous state in sibs with carnitine-acylcarnitine translocase deficiency (CACTD; 212138) by Huizing et al. (1998), see 613698.0002.
In a patient with severe carnitine-acylcarnitine translocase deficiency (CACTD; 212138), Costa et al. (1999) found a homozygous 558C-T transition in the CACT cDNA, resulting in a premature stop codon (arg166 to ter). The presence of this C-to-T transition was directly confirmed in genomic DNA of the patient and her parents by analyzing a PCR-amplified product of 211 bp encompassing the mutation.
In a patient with carnitine-acylcarnitine translocase deficiency (CACTD; 212138), Ogawa et al. (2000) identified compound heterozygous mutations in the SLC25A20 gene: a 1-bp deletion (146delT), leading to premature termination and resulting in a very immature CACT protein, and a splicing mutation (613698.0006). Fibroblasts were from the patient reported by Stanley et al. (1992).
In a patient with CACT deficiency (CACTD; 212138), Ogawa et al. (2000) found compound heterozygosity for a splice site mutation, a T-to-G transversion at the nucleotide -10 upstream from the splice acceptor site of intron 2, and a 146delT mutation (613698.0005).
In a Japanese patient who died of CACT deficiency, Fukushima et al. (2013) identified compound heterozygous mutations in the SLC25A20 gene: a T-to-G transversion in intron 2 (c.199-10T-G) and W192X (613698.0008). Each unaffected parent was heterozygous for 1 of the mutations.
In a Saudi patient with virtually complete CACT deficiency (CACTD; 212138) in fibroblasts, born to first-cousin parents, Al Aqeel et al. (2003) identified homozygosity for a 712A-G transition in the cDNA of the SLC25A20 gene, resulting in a glu238-to-arg (Q238R) substitution. The patient presented on the second day of life with nystagmus and hyperammonemia. Thickened interventricular septum of the heart was demonstrated. The patient died at 7 months of age as a result of cardiac arrhythmia; 3 sibs had previously died as neonates.
In an Arab male infant with CACT deficiency, Iacobazzi et al. (2004) demonstrated homozygosity for the Q238R mutation in the SLC25A20 gene. The proband was the third child of consanguineous parents. Their second child, a female, died in Saudi Arabia at 3 days of age with an illness similar to the one in the proband.
In a Japanese infant who died of carnitine-acylcarnitine translocase deficiency (CACTD; 212138), Fukushima et al. (2013) identified compound heterozygous mutations in the SLC25A20 gene: a c.576G-A transition in exon 6, resulting in a trp192-to-ter (W192X) substitution, and a T-to-G transversion in intron 1 (c.199-10T-G; 613698.0006), resulting in aberrant splicing. Each unaffected parent was heterozygous for 1 of the mutations. A second unrelated Japanese infant with the disorder was found to be compound heterozygous for W192X and a different splice site mutation (c.106-2A-T; 613698.0009) in intron 1. Each unaffected parent was heterozygous for 1 of the mutations. None of the mutations were found in 13 control individuals.
For discussion of the splice site mutation (c.106-2A-T) in intron 1 of the SLC25A20 gene that was found in compound heterozygous state in a patient with carnitine-acylcarnitine translocase deficiency (CACTD; 212138) by Fukushima et al. (2013), see 613698.0008.
Al Aqeel, A. I., Rashid, M. S., Ruiter, J. P., Ijlst, L., Wanders, R. J. A novel molecular defect of the carnitine acylcarnitine translocase gene in a Saudi patient. (Letter) Clin. Genet. 64: 163-165, 2003. [PubMed: 12859414] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00117.x]
Costa, C., Costa, J. M., Nuoffer, J. M., Slama, A., Boutron, A., Saudubray, J. M., Legrand, A., Brivet, M. Identification of the molecular defect in a severe case of carnitine-acylcarnitine carrier deficiency. J. Inherit. Metab. Dis. 22: 267-270, 1999. [PubMed: 10384384] [Full Text: https://doi.org/10.1023/a:1005590223680]
Fukushima, T., Kaneoka, H., Yasuno, T., Sasaguri, Y., Tokuyasu, T., Tokoro, K., Fukao, T., Saito, T. Three novel mutations in the carnitine-acylcarnitine translocase (CACT) gene in patients with CACT deficiency and in healthy individuals. J. Hum. Genet. 58: 788-793, 2013. [PubMed: 24088670] [Full Text: https://doi.org/10.1038/jhg.2013.103]
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Iacobazzi, V., Naglieri, M. A., Stanley, C. A., Wanders, R. J. A., Palmieri, F. The structure and organization of the human carnitine/acylcarnitine translocase (CACT) gene. Biochem. Biophys. Res. Commun. 252: 770-774, 1998. [PubMed: 9837782] [Full Text: https://doi.org/10.1006/bbrc.1998.9738]
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Ogawa, A., Yamamoto, S., Kanazawa, M., Takayanagi, M., Hasegawa, S., Kohno, Y. Identification of two novel mutations of the carnitine/acylcarnitine translocase (CACT) gene in a patient with CACT deficiency. J. Hum. Genet. 45: 52-55, 2000. [PubMed: 10697964] [Full Text: https://doi.org/10.1007/s100380050010]
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Tachibana, K., Kobayashi, Y., Tanaka, T., Tagami, M., Sugiyama, A., Katayama, T., Ueda, C., Yamasaki, D., Ishimoto, K., Sumitomo, M., Uchiyama, Y., Kohro, T., Sakai, J., Hamakubo, T., Kodama, T., Doi, T. Gene expression profiling of potential peroxisome proliferator-activated receptor (PPAR) target genes in human hepatoblastoma cell lines inducibly expressing different PPAR isoforms. Nucl. Recept. 3: 3, 2005. Note: Electronic Article. [PubMed: 16197558] [Full Text: https://doi.org/10.1186/1478-1336-3-3]
Tachibana, K., Takeuchi, K., Inada, H., Yamasaki, D., Ishimoto, K., Tanaka, T., Hamakubo, T., Sakai, J., Kodama, T., Doi, T. Regulation of the human SLC25A20 expression by peroxisome proliferator-activated receptor alpha in human hepatoblastoma cells. Biochem. Biophys. Res. Commun. 389: 501-505, 2009. [PubMed: 19748481] [Full Text: https://doi.org/10.1016/j.bbrc.2009.09.018]
Viggiano, L., Iacobazzi, V., Marzella, R., Cassano, C., Rocchi, M., Palmieri, F. Assignment of the carnitine/acylcarnitine translocase gene (CACT) to human chromosome band 3p21.31 by in situ hybridization. Cytogenet. Cell Genet. 79: 62-63, 1997. [PubMed: 9533014] [Full Text: https://doi.org/10.1159/000134684]