STRUCTURE AND FUNCTION OF ASP, THE HUMAN HOMOLOG OF THE MOUSE AGOUTI GENE

The mouse agouti coat color gene encodes a novel paracrine signaling m olecule whose pulsatile expression produces a characteristic pattern o f banded pigment in individual hairs. Several spontaneous agouti allel es produce adult-onset obesity and diabetes, and have provided importa nt single-gene animal models for alterations in energy metabolism. Uti lizing linkage groups conserved between mice and humans, we have clone d the human homolog of the mouse agouti gene from a human chromosome 2 0 yeast artificial chromosome known to contain S-adenosyl homocysteine hydrolase (AHCY). The human agouti gene, named Agouti Signaling Prote in (ASP) encodes a 132 amino acid protein, the mRNA for which is expre ssed in testis, ovary, and heart, and at lower levels in liver, kidney , and foreskin. As predicted by the interactions of mouse agouti with the extension gene (which encodes the melanocyte receptor for alpha-me lanocyte stimulating hormone [alpha-MSH]), expression of ASP in transg enic mice produces a yellow coat, and expression of ASP in cell cultur e blocks the alpha-MSH-stimulated accumulation of cAMP in mouse melano ma cells. The localization of ASP relative to other loci on chromosome 20 excludes it as a candidate for the MODY1 locus, a gene responsible for one form of early-onset non-insulin-dependent diabetes mellitus o r maturity-onset diabetes of the young. The expression of ASP in human tissues suggests a function for agouti homologs in species that do no t exhibit the characteristic phenotype of banded hairs.