Alternative titles; symbols
HGNC Approved Gene Symbol: ATRN
Cytogenetic location: 20p13 Genomic coordinates (GRCh38) : 20:3,471,018-3,651,118 (from NCBI)
Attractin is a human serum glycoprotein that is rapidly expressed on activated T cells and released extracellularly after 48 to 72 hours. Duke-Cohan et al. (1998) cloned attractin and found that, as in its natural serum form, it mediates the spreading of monocytes that becomes the focus for the clustering of nonproliferating T lymphocytes. There are 2 mRNA species with hematopoietic tissue-specific expression that code for a 134-kD protein with a putative serine protease catalytic serine, 4 EGF-like motifs, a CUB domain, a C-type lectin domain, and a domain homologous with the ligand-binding region of the common gamma cytokine chain. Except for the last 2 domains, the overall structure shares high homology with a protein of Caenorhabditis elegans, suggesting that attractin has evolved new domains and functions in parallel with the development of cell-mediated immunity.
Gunn et al. (1999) and Nagle et al. (1999) independently and simultaneously cloned the mouse 'mahogany' gene. Using a positional cloning strategy, Gunn et al. (1999) identified a mahogany candidate gene, Mgca, on chromosome 2. The normal 9-kb Mgca mRNA is expressed in brain, skin, heart, kidney, liver, and lung. The sequence of the extracellular domain of Mgca protein is 93% identical to the sequence of attractin. The peptide sequence of attractin terminates 6 codons after it diverges from Mgca and 11 codons before the transmembrane domain of Mgca. Using a probe corresponding to the amino-terminal region of mouse Mgca, Gunn et al. (1999) detected 2 main RNA isoforms of 8.5 and 4 kb in human tissues. They postulated that the 8.5-kb transcript is likely to encode the transmembrane form of human attractin because it is also detected by a probe corresponding to the Mgca C terminus. Gunn et al. (1999) also detected a human brain cDNA clone with 97% identity to the C-terminal 452 residues of Mgca. The site at which the attractin and human brain cDNAs diverge corresponds to a splice junction in the Mgca genomic sequence.
When attractin was identified as the product of the murine 'mahogany' gene with connections to control of pigmentation and energy metabolism, and the 'mahogany' product was identified and shown to be a transmembrane protein, the possibility of a human membrane attractin in addition to the secreted form was raised. Tang et al. (2000) described the complete genomic sequence of attractin, focusing in particular on the exons coding for the 3-prime region, and showed how both human membrane and secreted attractin arise as a result of alternate splicing of the same gene. They found that soluble attractin arises from transcription of 25 sequential exons on 20p13, where the 3-prime terminal exon contains sequence from a long interspersed nuclear element-1 (LINE-1) retrotransposon insertion that includes a stop codon and a polyadenylation signal. The mRNA isoform for membrane attraction splices over the LINE-1 exon and includes 5 exons encoding transmembrane and cytoplasmic domains with organization and coding potential almost identical to that of the mouse gene. The relative abundance of soluble and transmembrane isoforms measured by RT-PCR is differentially regulated in lymphoid tissues. Because activation of peripheral blood leukocytes with phytohemagglutinin induces strong expression of cell surface attractin followed by release of soluble attractin, these results suggested to Tang et al. (2000) that LINE-1 insertion, a genomic event unique to mammals, provided an evolutionarily mechanism for regulating cell interactions during an inflammatory reaction.
Agouti protein (600201), a paracrine signaling molecule normally limited to the skin, is ectopically expressed in 'lethal yellow, or A(y), mice and causes obesity by mimicking agouti-related protein (AGRP; 602311), found primarily in the hypothalamus. Loss of function of the mouse Atrn protein in mahogany mutant mice blocks the pleiotropic effects of A(y). He et al. (2001) demonstrated in transgenic, biochemical, and genetic-interaction experiments that attractin is a low affinity receptor for agouti protein, but not for Agrp, in vitro and in vivo. Additional histopathologic abnormalities in homozygous mahogany mice and cross-species genomic comparisons indicated that Atrn has multiple functions distinct from both a physiologic and an evolutionary perspective.
Nagle et al. (1999) emphasized the importance of Mgca expression in the ventromedial hypothalamic nucleus, a region central to the regulation of body weight and feeding. Nagle et al. (1999) demonstrated that the mahogany locus did not suppress the obese phenotype of the melanocortin-4 receptor (155541) null allele or those of the monogenic obese mouse models Lep-db, tub, and Cpe-fat. However, mahogany can suppress diet-induced obesity, the mechanism of which Nagle et al. (1999) suggested has implications for therapeutic intervention in human obesity.
Malik et al. (2001) determined that attractin mRNA and protein were expressed in rat and human glioma cell lines and noted that expression had not been found in normal glial cells. Biochemical characterization of attractin from human glioma cell lines showed that membrane-bound attractin had DPP4 (102720)-like hydrolytic activity. Flow cytometry revealed attractin present in cell lines that did not show DPP4-like activity, implying that attractin could be present in either enzymatically active or inactive forms.
By sequence homology and EST database searching, Tang et al. (2000) mapped the human ATRN gene to chromosome 20p13.
Duke-Cohan, J. S., Gu, J., McLaughlin, D. F., Xu, Y., Freeman, G. J., Schlossman, S. F. Attractin (DPPT-L), a member of the CUB family of cell adhesion and guidance proteins, is secreted by activated human T lymphocytes and modulates immune cell interactions. Proc. Nat. Acad. Sci. 95: 11336-11341, 1998. [PubMed: 9736737] [Full Text: https://doi.org/10.1073/pnas.95.19.11336]
Gunn, T. M., Miller, K. A., He, L., Hyman, R. W., Davis, R. W., Azarani, A., Schlessman, S. F., Duke-Cohan, J. S., Barsh, G. S. The mouse mahogany locus encodes a transmembrane form of human attractin. Nature 398: 152-156, 1999. [PubMed: 10086356] [Full Text: https://doi.org/10.1038/18217]
He, L., Gunn, T. M., Bouley, D. M., Lu, X.-Y., Watson, S. J., Schlossman, S. F., Duke-Cohan, J. S., Barsh, G. S. A biochemical function for attractin in agouti-induced pigmentation and obesity. Nature Genet. 27: 40-47, 2001. [PubMed: 11137996] [Full Text: https://doi.org/10.1038/83741]
Malik, R., Mares, V., Kleibl, Z., Pohlreich, P., Vlasicova, K., Sedo, A. Expression of attractin and its differential enzyme activity in glioma cells. Biochem. Biophys. Res. Commun. 284: 289-294, 2001. [PubMed: 11394875] [Full Text: https://doi.org/10.1006/bbrc.2001.4956]
Nagle, D. L., McGrail, S. H., Vitale, J., Woolf, E. A., Dussault, B. J., Jr., DiRocco, L., Holmgren, L., Montagno, J., Bork, P., Huszar, D., Fairchild-Huntress, V., Ge, P., Keilty, J., Ebelling, C., Baldini, L., Gilchrist, J., Burr, P., Carlson, G. A., Moore, K. J. The mahogany protein is a receptor involved in suppression of obesity. Nature 398: 148-151, 1999. [PubMed: 10086355] [Full Text: https://doi.org/10.1038/18210]
Tang, W., Gunn, T. M., McLaughlin, D. F., Barsh, G. S., Schlossman, S. F., Duke-Cohan, J. S. Secreted and membrane attractin result from alternative splicing of the human ATRN gene. Proc. Nat. Acad. Sci. 97: 6025-6030, 2000. [PubMed: 10811918] [Full Text: https://doi.org/10.1073/pnas.110139897]