International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F7 Genetic and Biochemical Studies of the Mahogany Gene

Gunn, T.M.1, He, L.1, Duke-Cohan, J.2, and Barsh, G.1 1HHMI, Beckman Center B281,Stanford University Medical Center, Stanford, CA 94305-5323; 2Division of Tumor Immunology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115

The mouse mahogany (mg) mutation causes a reduction in the synthesis of yellow pigment in the coat hairs and suppresses the effects of ectopic Agouti protein on both pigmentation and obesity; + Ay/+ + mice are obese and yellow whereas mg Ay/+ mg mice are lean and brown. Genetic epistasis studies indicate that mg lies downstream of Agouti but upstream of the Mc1r, a G protein-coupled receptor to which Agouti protein binds with high affinity. We have recently identified the mahogany gene as a widely expressed single transmembrane-spanning protein with limited sequence similarity to heparan sulfate proteoglycans, and have now carried out a series of molecular biologic, physiologic, and biochemical studies to determine its mechanism of action.

In mice the predominant form of Mahogany is a 1428-residue transmembrane protein but in humans there are two isoforms, one of which is truncated before the transembrane domain. Sequence analysis reveals a retrotransposon element in the intron before the exon encoding the beginning of the transmembrane-domain of the human gene; splicing over the element gives rise to the full-length protein while splicing into the element gives rise to the secreted form. Two of the mutant mouse alleles, mg and mgL, contain similar retrotransposon insertions and have a hypomorphic effect on pigmentation. These alleles may represent mouse models for the normal allele in humans. A third mouse allele, mg3-J, is amorphic with regard to pigmentation and causes increased physical activity and reduced body weight in homozygous animals, primarily due to decreased adiposity. Surprisingly, mg3-J has no effect on obesity caused by over-expression of Agouti-related protein, which is normally expressed in the hypothalamus and is responsible for the effects of ectopic Agouti protein on body weight. Biochemical studies demonstrate a low-affinity interaction between the Agouti and Mahogany proteins. Taken together, these data suggest that Mahogany acts as a low-affinity receptor for Agouti protein but that the effects of Mahogany on regulation of body weight are both central and peripheral.

 


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