Alternative titles; symbols
HGNC Approved Gene Symbol: CARTPT
Cytogenetic location: 5q13.2 Genomic coordinates (GRCh38) : 5:71,719,275-71,721,045 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q13.2 | {?Obesity, susceptibility to} | 601665 | Autosomal dominant; Autosomal recessive; Multifactorial | 3 |
CART appears to have roles in reward, feeding, and stress, and it has the functional properties of an endogenous psychostimulant (Kuhar et al., 2002).
Using rat Cart cDNA to probe a human hypothalamus cDNA library, followed by 5-prime RACE, Douglass and Daoud (1996) cloned human CART. The transcript has 3 poly(A)-recognition sites within the 3-prime UTR, and the deduced 116-amino acid protein contains an N-terminal signal peptide. Human CART shares 95% amino acid identity with one of the 2 rat Cart isoforms. The other Cart isoform, which is not present in human, has a 13-amino acid insertion encoded by an alternatively spliced transcript. Northern blot analysis of several human brain regions detected a major transcript of about 0.9 kb expressed at highest levels in hypothalamus, frontal cortex, and midbrain. Moderate to low expression was detected in hippocampus, motor cortex, and caudate putamen, and no expression was detected in cerebellum.
Douglass and Daoud (1996) determined that the CART gene contains 3 exons and spans about 2.0 kb. The promoter region contains a TATAAA box.
By examining human/rodent somatic cell hybrid panels, Douglass and Daoud (1996) mapped the CART gene to chromosome 5.
By analysis of a radiation hybrid panel, Echwald et al. (1999) mapped the CART gene to chromosome 5q13-q14.
Stumpf (2023) mapped the CARTPT gene to chromosome 5q13.2 based on an alignment of the CARTPT sequence (GenBank BC029882) with the genomic sequence (GRCh38).
The mammalian hypothalamus strongly influences ingestive behavior through several different signaling molecules and receptor systems. Kristensen et al. (1998) showed that Cart, a brain-located peptide, is a satiety factor and is closely associated with the actions of 2 important regulators of food intake, leptin (164160), and neuropeptide Y (162640). Food-deprived animals showed a pronounced decrease in expression of Cart mRNA in the arcuate nucleus. In animal models of obesity with disrupted leptin signaling, Cart mRNA was almost absent from the arcuate nucleus. Peripheral administration of leptin to obese mice stimulated Cart mRNA expression. When injected intracerebroventricularly into rats, recombinant Cart peptide inhibited both normal and starvation-induced feeding, and completely blocked the feeding response induced by neuropeptide Y. An antiserum against Cart increased feeding in normal rats, indicating that Cart may be an endogenous inhibitor of food intake in normal animals.
Elias et al. (1998) found that leptin activated Cart-containing neurons of the rat retrochiasmatic area and lateral arcuate nucleus of the hypothalamus. Most of the Cart-containing neurons also contained proopiomelanocortin (POMC; 176830) mRNA. Since these neurons innervate sympathetic preganglionic neurons in the thoracic spinal cord, Elias et al. (1998) hypothesized that leptin activation of this neural pathway may contribute to the increased thermogenesis, energy expenditure, and decreased body weight following leptin administration.
By analyzing Adrb2 (109690)-deficient mice, Elefteriou et al. (2005) demonstrated that the sympathetic nervous system favors bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl (602642). This sympathetic function requires phosphorylation by protein kinase A (PKA; see 176911) of ATF4 (604064), a cell-specific CREB (123810)-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biologic importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART, a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Elefteriou et al. (2005) concluded that their study established that leptin-regulated neural pathways control both aspects of bone remodeling, and demonstrated that integrity of sympathetic signaling is necessary for the increase in bone resorption caused by gonadal failure.
Challis et al. (2000) sequenced the entire coding region of CART in 91 unrelated subjects with severe early-onset obesity. A novel amino acid change, ser66 to thr, was found in 2 probands and in 0 of 100 control subjects but did not segregate with obesity in family studies. Challis et al. (2000) also found 2 common polymorphisms in the 3-prime untranslated region (UTR), 1475A-G and 1457delA. Neither polymorphism showed any significant relationship with obesity. Echwald et al. (1999) had identified these 3-prime UTR polymorphisms and found no association with obesity in a large Danish Caucasian cohort.
Del Giudice et al. (2001) screened the CART gene by SSCP and automatic sequencing in 130 (72 girls) unrelated obese Italian children and adolescents. The mean of their Z scores relative to body mass index (BMI) percentiles was 3.9 +/- 1.8, and the average age at obesity onset was 4.7 +/- 2.6 years. They also identified two 3-prime untranslated polymorphisms: 1457delA with an allele frequency 0.035 and the A-to-G substitution at position 1475 in 11 patients with an allele frequency of 0.042. Del Giudice et al. (2001) found no difference between the obese patients heterozygous for one of these polymorphisms and those patients homozygous for the wildtype allele with respect to their age of obesity onset, BMI Z-scores, and leptin levels. They identified a missense mutation, leu34 to phe (602606.0001) in the N-terminal CART region in heterozygous state in an obese 10-year-old boy who had been obese since the age of 2 years. The patient belonged to a large family of obese subjects. The mutation cosegregated with a severe obesity phenotype over 3 generations and was not found in the control population. Resting metabolic rates were lower than expected in the propositus (-14%) and his mother (-16%), who carried the mutation. Leucine at codon 34, conserved in this position in the human and rat sequences, immediately precedes 2 lysine residues that may well represent a dibasic processing site.
Walder et al. (2000) screened the human CART gene and identified a novel C-to-G substitution in the 3-prime UTR of exon 3. This polymorphism was genotyped in a total of 68 Pima Indians with extremes of BMI. The frequencies for alleles C and G were 0.76 and 0.24, respectively. There was no evidence of an association between the genotype frequency at this variant and extremes of BMI in this group of Pima Indians. Walder et al. (2000) concluded that the results of this study do not suggest a significant role for this variant in exon 3 of CART as a determinant of obesity in Pima Indians.
Yamada et al. (2002) screened the 5-prime flanking region and coding regions of CART to detect polymorphisms. Six polymorphic sites were identified; an A-to-G substitution at position -156 was significantly associated with a greater BMI (p = 0.036). The allele frequency of the -156 variant was significantly higher in obese subjects with BMI greater than 30 than in nonobese subjects (0.41 vs 0.32, p = 0.0076). No mutations were identified in the coding regions.
In fed and food-deprived mice, Jean et al. (2007) showed that direct stimulation of Htr4 receptors (602164) in the nucleus accumbens reduced the physiologic drive to eat and increased Cart mRNA levels. Injection of Htr4 antagonist or siRNA-mediated Htr4 knockdown targeted to the nucleus accumbens induced hyperphagia only in fed mice and did not affect CART mRNA expression. Injection of CART peptide or siRNA-mediated CART knockdown targeted to the nucleus accumbens reduced or increased food consumption, respectively. Jean et al. (2007) concluded that HTR4-induced anorexia is mediated by CART in the nucleus accumbens.
In an obese (601665) 10-year-old Italian boy whose onset of obesity had been at the age of 2 years, Del Giudice et al. (2001) identified a G-to-C transversion at nucleotide 729 of the CART gene resulting in a leucine to phenylalanine substitution at codon 34 (L34F). The leucine at this position is conserved in human and rat. The L34F mutation segregated with severe obesity over 3 generations in this family and was not identified in the control population. Both he and his mother were found to have reduced resting energy expenditures.
Dominguez et al. (2004) transfected mouse pituitary corticotroph cells with wildtype CART and CART carrying the L34F mutation. They found that CART peptide levels in cells carrying the mutation were lower than levels found in cells carrying wildtype CART.
Challis, B. G., Yeo, G. S. H., Farooqi, I. S., Luan, J., Aminian, S., Halsall, D. J., Keogh, J. M., Wareham, N. J., O'Rahilly, S. The CART gene and human obesity: mutational analysis and population genetics. Diabetes 49: 872-875, 2000. [PubMed: 10905499] [Full Text: https://doi.org/10.2337/diabetes.49.5.872]
del Giudice, E., Santoro, N., Cirillo, G., D'Urso, L., Di Toro, R., Perrone, L. Mutational screening of the CART gene in obese children: identifying a mutation (leu34phe) associated with reduced resting energy expenditure and cosegregating with obesity phenotype in a large family. Diabetes 50: 2157-2160, 2001. [PubMed: 11522684] [Full Text: https://doi.org/10.2337/diabetes.50.9.2157]
Dominguez, G., del Giudice, E. M., Kuhar, M. J. CART peptide levels are altered by a mutation associated with obesity at codon 34. Molec. Psychiat. 9: 1065-1066, 2004. [PubMed: 15326462] [Full Text: https://doi.org/10.1038/sj.mp.4001578]
Douglass, J., Daoud, S. Characterization of the human cDNA and genomic DNA encoding CART: a cocaine- and amphetamine-regulated transcript. Gene 169: 241-245, 1996. [PubMed: 8647455] [Full Text: https://doi.org/10.1016/0378-1119(96)88651-3]
Echwald, S. M., Sorensen, T. I., Andersen, T., Hansen, C., Tommerup, N., Pedersen, O. Sequence variants in the human cocaine and amphetamine-regulated transcript (CART) gene in subjects with early onset obesity. Obes. Res. 7: 532-536, 1999. [PubMed: 10574510] [Full Text: https://doi.org/10.1002/j.1550-8528.1999.tb00710.x]
Elefteriou, F., Ahn, J. D., Takeda, S., Starbuck, M., Yang, X., Liu, X., Kondo, H., Richards, W. G., Bannon, T. W., Noda, M., Clement, K., Vaisse, C., Karsenty, G. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434: 514-520, 2005. [PubMed: 15724149] [Full Text: https://doi.org/10.1038/nature03398]
Elias, C. F., Lee, C., Kelly, J., Aschkenasi, C., Ahima, R. S., Couceyro, P. R., Kuhar, M. J., Saper, C. B., Elmquist, J. K. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 21: 1375-1385, 1998. [PubMed: 9883730] [Full Text: https://doi.org/10.1016/s0896-6273(00)80656-x]
Jean, A., Conductier, G., Manrique, C., Bouras, C., Berta, P., Hen, R., Charnay, Y., Bockaert, J., Compan, V. Anorexia induced by activation of serotonin 5-HT(4) receptors is mediated by increases in CART in the nucleus accumbens. Proc. Nat. Acad. Sci. 104: 16335-16340, 2007. [PubMed: 17913892] [Full Text: https://doi.org/10.1073/pnas.0701471104]
Kristensen, P., Judge, M. E., Thim, L., Ribel, U., Christjansen, K. N., Wulff, B. S., Clausen, J. T., Jensen, P. B., Madsen, O. D., Vrang, N., Larsen, P. J., Hastrup, S. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393: 72-76, 1998. [PubMed: 9590691] [Full Text: https://doi.org/10.1038/29993]
Kuhar, M. J., Adams, S., Dominguez, G., Jaworski, J., Balkan, B. CART peptides. Neuropeptides 36: 1-8, 2002. [PubMed: 12147208] [Full Text: https://doi.org/10.1054/npep.2002.0887]
Stumpf, A. M. Personal Communication. Baltimore, Md. 12/01/2023.
Walder, K., Morris, C., Ravussin, E. A polymorphism in the gene encoding CART is not associated with obesity in Pima Indians. Int. J. Obes. Relat. Metab. Disord. 24: 520-521, 2000. [PubMed: 10805512] [Full Text: https://doi.org/10.1038/sj.ijo.0801196]
Yamada, K., Yuan, X., Otabe, S., Koyanagi, A., Koyama, W., Makita, Z. Sequencing of the putative promoter region of the cocaine- and amphetamine-regulated-transcript gene and identification of polymorphic sites associated with obesity. Int. J. Obes. Relat. Metab. Disord. 26: 132-136, 2002. [PubMed: 11791158] [Full Text: https://doi.org/10.1038/sj.ijo.0801848]