ASIP gene

The ASIP gene (ASIP stands for: Agouti Signaling Protein) is a protein-coding gene located on chromosome 20q11.22. An important paralog of this gene is AGRP.

In mice, the agouti gene encodes a paracrine signaling molecule that induces the melanocytes of the hair follicles to synthesize the yellow pigment pheomelanin instead of the black or brown pigment eumelanin.

The pleiotropic effects of constitutive expression of the mouse gene include obesity in adulthood, increased susceptibility to tumors and premature infertility.

In humans, this gene is very similar to the mouse gene and encodes a secreted protein that can influence the quality of hair pigmentation and also acts as a pharmacological antagonist of alpha-melanocyte-stimulating hormone. Agouti signaling protein plays a role in the neuroendocrine aspects of melanocortin action and has a functional role in the regulation of lipid metabolism in adipocytes.

Diseases associated with ASIP include variations in skin/hair/eye pigmentation as well as obesity and hypopigmentation. Related signaling pathways include insulin-mediated glucose transport and GPR143 in melanocytes and retinal pigment epithelial cells.

The Agouti signaling protein is involved in the regulation of melanogenesis. Its effect on pigmentation is achieved by antagonizing the binding of alpha-melanocyte-stimulating hormone (alpha-MSH) to the melanocortin-1 receptor (Mc1r), thereby switching melanin synthesis from eumelanin (black/brown) to phaeomelanin (red/yellow) (Voisey J et al. 2002). In higher primates, agouti may influence the quality of hair pigmentation rather than its pattern of deposition. Dominant mutations in the non-coding region of mouse agouti cause yellow coat color, and ectopic expression also leads to obesity, type 11 diabetes, increased somatic growth and tumor formation. The yellow coat color is the result of chronic antagonization of the binding of alpha-MSH to Mc1r by agouti, and the obese phenotype is the result of antagonization of the binding of alpha-MSH to Mc3r and/or Mc4r by the agouti protein.

Although there is a highly homologous agouti protein in humans, the agouti signaling protein (ASIP), its role is ultimately not yet clear. However, it is known that human ASIP is most highly expressed in adipose tissue, where it may antagonize one of the melanocortin receptors (Voisey J et al. 2002).

Recently, a heterozygous tandem duplication at the ASIP gene locus (agouti signaling protein) was reported to cause ubiquitous, ectopic ASIP expression in a patient with extreme childhood obesity. The patient's phenotype of early-onset obesity, excessive growth, red hair and hyperinsulinemia is consistent with that of mutant mice ubiquitously expressing the nonagouti homolog. ASIP, as a melanocortin receptor antagonist, suppresses melanocyte-stimulating hormone activation, which could affect eating behavior, energy expenditure, adipocyte differentiation and pigmentation, as observed in the index patient (Kempf E et al. 2022).

1. Froguel P et al. (2022) The discovery of human agouti-induced obesity and its implication for genetic diagnosis. Nat Metab 4:1614-1615.
2. Kempf E et al. (2022) Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity. Nat Metab 4:1697-1712.
3. Norris BJ et al. (2008) A gene duplication affecting expression of the ovine ASIP gene is responsible for white and black sheep. Genome Res 18:1282-1293.
4. Voisey J et al. (2002) from mouse to man, from skin to fat. Pigment Cell Res 15:10-18.