Online Mendelian Inheritance in Man (OMIM) (original) (raw)

Cytogenetic location: 20q11.22 Genomic coordinates (GRCh38) : 20:34,186,493-34,269,344 (from NCBI)

TEXT

Cloning and Expression

The study of mouse coat color genes and their interactions provides insights into many processes relevant to human development and disease. The agouti gene on mouse chromosome 2 encodes a paracrine signaling molecule that causes hair follicle melanocytes to synthesize pheomelanin, a yellow pigment, instead of the black or brown pigment eumelanin. Consequently, agouti mice produce hairs with a subapical yellow band on an otherwise black or brown background when expressed during the midportion of hair growth. The cloned mouse agouti gene encodes a distinctive 131-amino acid protein with a consensus signal peptide, indicating that the protein is probably secreted (Kwon et al., 1994). It is normally expressed in neonatal skin. In most mice, agouti is expressed at highest levels in skin and is under control of hair cycle- and ventral-specific promoters, which together produce a light-bellied phenotype, i.e., a combination of yellow ventral hairs and banded dorsal hairs. In several mouse mutations, such as 'lethal yellow' and 'viable yellow,' agouti is deregulated and expressed ectopically. Expression throughout hair growth and in nearly every tissue of the body produces a yellow coat and pleiotropic effects that include adult-onset obesity, increased tumor susceptibility, and premature infertility.

Using an interspecies DNA-hybridization approach, Kwon et al. (1994) cloned the human homolog of the mouse agouti gene. Sequence analysis demonstrated that the coding region of the human gene is 85% identical to that of the mouse gene and has the potential to encode a protein of 132 amino acids with a consensus signal peptide. Expression studies with RNA from several adult human tissues showed that the gene is expressed in adipose tissues and testis. The question of a functional role in the regulation of lipid metabolism within the adipocyte was raised, and the mapping to the same region as the locus for MODY1 (125850) was noted.

Using linkage groups conserved between mice and humans, Wilson et al. (1995) cloned the human homolog of the mouse agouti gene from a human chromosome 20 YAC known to contain S-adenosylhomocysteine hydrolase (180960), located on 20cen-q13.1 and known to be closely linked to agouti in mouse. They named the human homolog 'agouti signaling protein' (ASP) and confirmed that it encodes a 132-amino acid protein. They showed, furthermore, that its mRNA is expressed in testes, 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-melanocyte stimulating hormone (MC1R; 155555), expression of ASP in transgenic mice produced a yellow coat, and expression of ASP in cell culture blocked the MC1R-stimulated accumulation of cAMP in mouse melanoma cells. The localization of ASP on chromosome 20cen-q13.1 relative to other 20q loci excluded it as a candidate for the MODY1 locus, which maps to 20q12-q13.1.

Mapping

Kwon et al. (1994) mapped the human agouti gene to chromosome 20q11.2 by somatic cell hybrid mapping panels and fluorescence in situ hybridization.

Gene Function

Zemel et al. (1995) examined the status of intracellular Ca(2+) in mice carrying the dominant agouti allele, viable yellow, since intracellular Ca(2+) is believed to play a role in mediating insulin action and dysregulation of Ca(2+) flux is observed in diabetic animals and humans. They showed that in mice carrying this mutation, intracellular free calcium concentration is elevated in skeletal muscle, and the degree of elevation is closely correlated with the degree to which the mutant traits are expressed in individual animals. They also demonstrated that the agouti gene product is capable of inducing increased intracellular free calcium in cultured and freshly isolated skeletal muscle myocytes from wildtype mice. Based on these findings, Zemel et al. (1995) proposed that the agouti polypeptide promotes insulin resistance in mutant animals through its ability to increase intracellular calcium ion.

Manne et al. (1995) reviewed the mechanisms for the pleiotropic effects of the agouti gene and discussed the implications for human disease. Expression of the human agouti gene was detected in adipose tissue, heart, and testis, suggesting a role in a variety of processes including skin pigmentation, cardiovascular function, and energy metabolism. In addition, the observation of agouti expression in premenopausal but not postmenopausal ovaries suggested a role for the agouti protein in fertility as well. Observations of elevated intracellular calcium ion levels in tissues from hypertensive, obese, and diabetic patients suggest that the agouti protein may be a common link between these diseases. The level of expression of the agouti gene may be dictated by a series of alleles in the human population that can predispose individuals to obesity, cardiovascular disease, and/or diabetes.

Graham et al. (1997) stated that the ectopic expression of agouti produces obesity by mimicking the normal action of AGRT (602311) in the hypothalamus.

Chronic antagonism of melanocortin receptors by the paracrine-acting agouti gene product induces both yellow fur and a maturity-onset obesity syndrome in mice that ubiquitously express wildtype agouti. Functional analysis of agouti mutations in transgenic mice indicate that the cysteine-rich C terminus, signal peptide, and glycosylation site are required for agouti activity in vivo. In contrast, no biologic activity has been ascribed to the conserved basic domain consisting of approximately 30 amino acids of predominantly basic residues in the center of the protein in all mammals in which it has been studied. To examine the functional significance of the agouti basic domain in the mouse, Miltenberger et al. (1999) deleted the entire 29-amino acid region from the agouti cDNA, and the resulting mutation was expressed in transgenic mice under the control of the human beta-actin promoter. Three independent lines of mutant transgenic mice all developed some degree of yellow pigment in the fur, indicating that the mutant protein was functional in vivo. However, none of the mutant transgenic mice developed completely yellow fur, obesity, hyperinsulinism, or hyperglycinemia. High levels of expression of the mutant protein in relevant tissues exceeded the level of agouti expression in obese viable yellow mice, suggesting that suboptimal activity or synthesis of the mutant protein, rather than insufficient RNA synthesis, accounted for the phenotype of the mutant transgenic mice. These findings indicated a functional role for the agouti basic domain in vivo, possibly influencing the biogenesis of secreted agouti protein or modulating protein-protein interactions that contribute to effective antagonism of melanocortin receptors.

Epigenetic modifications have effects on phenotype, but they are generally considered to be cleared on passage through the germline in mammals, so that only genetic traits are inherited. Morgan et al. (1999) describe the inheritance of an epigenetic modification at the agouti locus in mice. In viable yellow mice, transcription originating in an intracisternal A particle (IAP) retrotransposon inserted upstream of the agouti gene causes ectopic expression of agouti protein, resulting in yellow fur, obesity, diabetes, and increased susceptibility to tumors. The pleiotropic effects of ectopic agouti expression are presumably due to effects of the paracrine signal on other tissues. Viable yellow mice display variable expressivity because they are epigenetic mosaics for activity of the retrotransposon. Isogenic viable yellow mice have coats that vary in a continuous spectrum from full yellow through variegated yellow/agouti to full agouti (pseudoagouti). The distribution of phenotypes among offspring is related to the phenotype of the dam, and when a viable yellow dam has the agouti phenotype, her offspring are more likely to be agouti. Morgan et al. (1999) demonstrated that this maternal epigenetic effect is not the result of a maternally contributed environment. By using an alternative combination of genetic and embryo-transfer experiments, Morgan et al. (1999) found that the nonrandom distribution of coat color results from an incomplete erasure of an epigenetic modification when a silenced viable yellow allele is passed through the female germline, with consequent inheritance of the epigenetic modification. Morgan et al. (1999) suggested that since retrotransposons are abundant in mammalian genomes, this type of inheritance may be common.

In mouse follicular melanocytes, production of eumelanins and pheomelanins is under the control of 2 intercellular signaling molecules that exert opposite actions: alpha-MSH (see 176830), which preferentially increases the synthesis of eumelanins, and ASP, whose expression favors the production of hair containing pheomelanins. Aberdam et al. (1998) reported that ASP not only affects mature melanocytes but can also inhibit the differentiation of melanoblasts. They showed that both alpha-MSH and forskolin promote the differentiation of murine melanoblasts into mature melanocytes, and that ASP inhibits this process. Expression of MITF (156845) and its binding to an M-box regulatory element is inhibited by ASP. Aberdam et al. (1998) also showed that in a murine melanoma cell line, ASP inhibits alpha-MSH-stimulated expression of tyrosinase (see 606933), TYRP1 (115501), and TYRP2 (191275) through an inhibition of the transcriptional activity of their respective promoters. Further, ASP inhibits alpha-MSH-induced expression of the MITF gene and reduces the level of MITF in the cells. Aberdam et al. (1998) concluded that ASP can regulate both melanoblast differentiation and melanogenesis, pointing out the key role of MITF in the control of these processes.

Cytogenetics

In a 16-year-old girl with early-onset severe obesity and hypopigmentation (OBHP; 620195), who was negative for mutation in monogenic obesity-associated genes, Kempf et al. (2022) performed trio whole-genome sequencing, copy-number variation screening, and cloning of breakpoint sequence, and identified heterozygosity for a 183-kb tandem duplication on chromosome 20 that encompassed the ASIP and ITCH (606409) genes on the forward strand and AHCY (180960) on the reverse strand. Quantitative RT-PCR in patient SVF and peripheral blood cells showed an approximately 1.5-fold increase in AHCY expression and no difference in ITCH expression compared to control, whereas ASIP was overexpressed several hundredfold; the authors noted that this was consistent with the genomic rearrangement, which resulted in 3 copies of the AHCY gene, no change in the number of ITCH coding exons, and a switch of promoter usage driving ASIP gene expression by the ubiquitously active ITCH promoter. The duplication was inherited from her affected father, in whom ectopic expression of ASIP was confirmed. Targeted screening of 1,745 individuals from the Leipzig Childhood Obesity cohort revealed 4 additional patients carrying the same genomic rearrangement; RNA from peripheral blood was available for 3 of the patients, and ectopic ASIP expression was confirmed in all 3. All 4 patients experienced severe childhood obesity, and had BMI SDS above the median for the cohort; 3 had red or reddish-brown hair and 1 had brown hair. Experiments in transfected CHO-K1 cells demonstrated reduction of basal activity of both MC1R (155555) and MC4R (155541) with increasing concentrations of ASIP, supporting the hypothesis that ectopic ASIP antagonizes MC4R signaling in the hypothalamus, impairing processes related to eating behavior and energy expenditure and resulting in the obesity phenotype.

Molecular Genetics

In mice and humans, binding of alpha-melanocyte-stimulating hormone to the melanocyte-stimulating-hormone receptor (MSHR), the protein product of the melanocortin-1 receptor (MC1R; 155555) gene, leads to the synthesis of eumelanin. In the mouse, ligation of MSHR by ASP results in the production of pheomelanin. The binding of ASP to MSHR precludes alpha-MSH-initiated signaling and thus blocks production of cAMP, leading to a downregulation of eumelanogenesis. The net result is increased synthesis of pheomelanin. Kanetsky et al. (2002) undertook to characterize the ASIP gene in a group of white subjects to assess whether ASIP was a determinant of human pigmentation and whether this gene is associated with increased melanoma risk. They found no evidence of coding region sequence variation in ASIP, but detected an 8818A-G polymorphism in the 3-prime untranslated region (rs6058017; 600201.0001). They genotyped 746 participants in a study of melanoma susceptibility for this polymorphism. Among 147 healthy controls, the frequency of the G allele was 0.12. Carriage of the G allele was significantly associated with dark hair (odds ratio 1.8) and brown eyes (odds ratio 1.9) after adjusting for age, gender, and disease status. This was said to be the first report of an association of ASIP with specific human pigmentation characteristics. It remained to be investigated whether the interaction of MC1R and ASIP can enhance prediction of human pigmentation and melanoma risk.

In a large genomewide association study of human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals, Sulem et al. (2008) found strong association of an extended haplotype tagged by a 2-SNP haplotype, rs1015362G and rs4911414T, with red hair color, freckling, and skin sensitivity to sun, in addition to burning and freckling. The association was stronger than that found for rs6058017, and after adjustment for the ASIP haplotype, rs6058017 was only marginally associated with pigmentation characteristics. The SNPs rs1015362 and rs4911414 lie outside the ASIP gene itself.

Gudbjartsson et al. (2008) found association of the ASIP haplotype of Sulem et al. (2008) with susceptibility to cutaneous malignant melanoma and basal cell carcinoma (see CMM7, 612263).

Evolution

Linnen et al. (2009) studied cryptically colored deer mice living on the Nebraska Sand Hills, a dune field with soil mostly consisting of quartz grains that are lighter in color than the surrounding soils. The authors showed that the light coloration of these mice stems from a novel banding pattern on individual hairs produced by an increase in Agouti expression. This increase is caused by a cis-acting mutation (or mutations), which either is or is closely linked to a single amino acid deletion in Agouti that appears to be under selection. Linnen et al. (2009) noted that their data suggests that this derived Agouti allele arose de novo after the formation of the Sand Hills, which date to between 8,000 to 15,000 years ago. Linnen et al. (2009) concluded that their findings revealed one means by which genetic, developmental, and evolutionary mechanisms can drive rapid adaptation under ecologic pressure.

Animal Model

Mice that carry the lethal yellow or viable yellow mutation, 2 dominant mutations of the agouti gene on mouse chromosome 2, exhibit a phenotype that includes yellow fur, marked obesity, a form of type II diabetes associated with insulin resistance, and an increased susceptibility to tumor development. Klebig et al. (1995) generated transgenic mice that ectopically expressed an agouti cDNA clone encoding the normal agouti protein in all tissues examined. Transgenic mice of both sexes had yellow fur, became obese, and developed hyperinsulinemia. In addition, male transgenic mice developed hyperglycemia by 12 to 20 weeks of age. The results demonstrated that the ectopic agouti expression is responsible for most, if not all, of the phenotypic traits of the dominant, 'obese yellow' mutants.

Eizirik et al. (2003) studied the molecular genetics and evolution of melanism in the cat family. Melanistic coat coloration occurs as a common polymorphism in 11 of 37 felid species and reaches high population frequency in some cases but never achieves complete fixation. Eizirik et al. (2003) mapped, cloned, and sequenced the cat homologs of 2 putative candidate genes for melanism, ASIP (agouti) and melanocortin-1 receptor (MC1R; 155555), and identified 3 independent deletions associated with dark coloration in 3 different felid species. Association and transmission analyses showed that a 2-bp deletion in the ASIP gene specifies black coloration in domestic cats, and 2 different in-frame deletions in the MC1R gene are implicated in melanism in jaguars and jaguarundis. Melanistic individuals from 5 other felid species did not carry any of these mutations, implying that there are at least 4 independent genetic origins for melanism in the cat family. The inferred multiple origins and independent historical elevation in population frequency of felid melanistic mutations suggested the occurrence of adaptive evolution of this visible phenotype in a group of related free-ranging species.

Drogemuller et al. (2006) identified a mutation in the noncoding region of the Asip gene as the cause of black-and-tan coat pigmentation in Mangalitza pigs.

The agouti-yellow (Ay) deletion is the only genetic modifier known to suppress testicular germ cell tumor (TGCT; 273300) susceptibility in mice or human. The Ay mutation deletes Raly and Eif2s2 (603908) and induces the ectopic expression of agouti, all of which are potential TGCT-modifying mutations. Heaney et al. (2009) reported that the reduced TGCT incidence of heterozygous Ay male mice and the recessive embryonic lethality of Ay are caused by the deletion of Eif2s2. The incidence of affected males was reduced 2-fold in mice that were partially deficient for Eif2s2 and that embryonic lethality occurred near the time of implantation in mice that were fully deficient for Eif2s2. In contrast, neither reduced expression of Raly in gene-trap mice nor ectopic expression of agouti in transgenic or viable-yellow (Avy) mutants affected TGCT incidence or embryonic viability. Partial deficiency of Eif2s2 attenuated germ cell proliferation and differentiation, both of which are important to TGCT formation. Heaney et al. (2009) concluded that germ cell development and TGCT pathogenesis are sensitive to the availability of the eIF2 translation initiation complex and to changes in the rate of translation.

See melanocortin-4 receptor (MC4R; 155541) for further discussion of models for mouse obesity involving agouti.

Snowshoe hares (Lepus americanus) maintain seasonal camouflage by molting to a white winter coat, but some hares remain brown during the winter in regions with low snow cover. Jones et al. (2018) showed that cis-regulatory variation controlling seasonal expression of the agouti gene underlies this adaptive winter camouflage polymorphism. Genetic variation at agouti clustered by winter coat color across multiple hare and jackrabbit species, revealing a history of recurrent interspecific gene flow. Brown winter coats in snowshoe hares likely originated from an introgressed black-tailed jackrabbit (L. californicus) allele that has swept to high frequency in mild winter environments. Jones et al. (2018) concluded that these discoveries showed that introgression of genetic variants that underlie key ecologic traits can seed past and ongoing adaptation to rapidly changing environments.

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