Alternative titles; symbols
HGNC Approved Gene Symbol: CRAT
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38) : 9:129,094,794-129,110,793 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | ?Neurodegeneration with brain iron accumulation 8 | 617917 | Autosomal recessive | 3 |
Carnitine acyltransferases are a group of enzymes that catalyze the reversible transfer of acyl groups from an acyl-CoA thioester to carnitine, thus forming the corresponding acylcarnitine. These enzymes can be distinguished according to their substrate specificity in carnitine palmitoyltransferase (see CPT1, 600528 and CPT2, 600650), carnitine octanoyltransferase (CROT; 606090), and carnitine acetyltransferase (EC 2.3.1.7). CRAT is a key enzyme for metabolic pathways involved with the control of the acyl-CoA/CoA ratio in mitochondria, peroxisomes, and endoplasmic reticulum.
Corti et al. (1994) used a combination of PCR screening of cDNA libraries and RT-PCR to clone the human cDNA for human carnitine acetyltransferase. The cDNA (2,436 bp) hybridized to an mRNA species of approximately 2.9 kb that is particularly abundant in skeletal muscle and encodes a 68-kD protein containing a peroxisomal targeting signal.
Van der Leij et al. (2000) reviewed the function, structural features, and phylogenetics of human carnitine acyltransferase genes, including CRAT.
Acetylcarnitine, which can be a precursor for acetylcholine synthesis catalyzed by choline acetyltransferase, is thought to slow the rate of mental deterioration in Alzheimer patients, and Kalaria and Harik (1992) found decreased function of CRAT in the brain of Alzheimer patients.
Jogl and Tong (2003) reported the crystal structures of murine Crat alone and in complex with its substrate carnitine or with CoA. The Crat structure contains 2 domains that share the same backbone fold, similar to the structures of chloramphenicol acetyltransferase and dihydrolipoyl transacetylase (see 608770). The active site is located at the interface between the 2 domains. Carnitine and CoA are bound in deep channels in the enzyme, on opposite sides of the catalytic his343 residue. The authors concluded that the structural information provides a molecular basis for understanding the catalysis by CARTs and for designing their inhibitors, and it specifically suggests that the substrate carnitine may assist the catalysis by stabilizing the oxyanion in the reaction intermediate.
By FISH, Corti et al. (1994) mapped the CRAT gene to chromosome 9q34.1.
In a girl (patient 3), born of consanguineous Turkish parents, with neurodegeneration with brain iron accumulation-8 (NBIA8; 617917), Drecourt et al. (2018) identified a homozygous missense mutation in the CRAT gene, resulting in an arg321-to-his (R321H; 600184.0001). The mutation was found by exome sequencing. Patient cells showed decreased beta-oxidation of palmitate compared to controls, and knockdown of CRAT using siRNA in HeLa cells resulted in markedly decreased beta-oxidation compared to controls. These defects could be rescued by wildtype CRAT. Patient fibroblasts showed a 10-fold increase in iron content compared to controls when incubated with iron. In response to high iron, patient cells showed a normal and appropriate decrease in transferrin receptor (TFRC; 190010) mRNA levels, but the amount of TFRC did not decrease in patient cells, suggesting impaired posttranslational lysosomal-based degradation of TFRC. Patient cells showed impaired transferrin (190000) and TFRC trafficking and recycling compared to controls, with clustering at the surface and in the perinuclear region, as well as abnormally enlarged lysosomes. Patient cells also showed decreased palmitoylation of TFRC, which is necessary for regulating TFRC endocytosis. Addition of the antimalarial agent artesunate rescued abnormal TFRC palmitoylation and decreased iron content in cultured patient fibroblasts. Similar findings were observed in studies of cells from NBIA patients due to mutations in other NBIA-associated genes. Drecourt et al. (2018) concluded that certain forms of NBIA result from defective endosomal recycling and should be regarded as a disorder of cellular trafficking.
In a girl (patient 3), born of consanguineous Turkish parents, with neurodegeneration with brain iron accumulation-8 (NBIA8; 617917), Drecourt et al. (2018) identified a homozygous c.962G-A transition (c.962G-A, NM_000755.4) in the CRAT gene, resulting in an arg321-to-his (R321H) substitution at a highly conserved residue. The mutation, which was found by exome sequencing, was found at a low frequency in the dbSNP, ExAC, and Exome Sequencing Project (ESP) databases (0.0042% in ExAC and 0.0001 in ESP). It was not found in 200 control chromosomes. Immunoblot analysis failed to detect CRAT in patient fibroblasts. Patient cells showed decreased beta-oxidation of palmitate compared to controls, and knockdown of CRAT using siRNA in HeLa cells resulted in markedly decreased beta-oxidation compared to controls. These defects could be rescued by wildtype CRAT. Patient fibroblasts showed a 10-fold increase in iron content compared to controls when incubated with iron.
Corti, O., Finocchiaro, G., Rossi, E., Zuffardi, O., DiDonato, S. Molecular cloning of cDNAs encoding human carnitine acetyltransferase and mapping of the corresponding gene to chromosome 9q34.1. Genomics 23: 94-99, 1994. [PubMed: 7829107] [Full Text: https://doi.org/10.1006/geno.1994.1463]
Drecourt, A., Babdor, J., Dussiot, M., Petit, F., Goudin, N., Garfa-Traore, M., Habarou, F., Bole-Feysot, C., Nitschke, P., Ottolenghi, C., Metodiev, M. D., Serre, V., Desguerre, I., Boddaert, N., Hermine, O., Munnich, A., Rotig, A. Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation. Am. J. Hum. Genet. 102: 266-277, 2018. [PubMed: 29395073] [Full Text: https://doi.org/10.1016/j.ajhg.2018.01.003]
Jogl, G., Tong, L. Crystal structure of carnitine acetyltransferase and implications for the catalytic mechanism and fatty acid transport. Cell 112: 113-122, 2003. [PubMed: 12526798] [Full Text: https://doi.org/10.1016/s0092-8674(02)01228-x]
Kalaria, R. N., Harik, S. I. Carnitine acetyltransferase activity in the human brain and its microvessels is decreased in Alzheimer's disease. Ann. Neurol. 32: 583-586, 1992. [PubMed: 1456745] [Full Text: https://doi.org/10.1002/ana.410320417]
van der Leij, F. R., Huijkman, N. C. A., Boomsma, C., Kuipers, J. R. G., Bartelds, B. Genomics of the human carnitine acyltransferase genes. Molec. Genet. Metab. 71: 139-153, 2000. [PubMed: 11001805] [Full Text: https://doi.org/10.1006/mgme.2000.3055]