The mahogany protein is a receptor involved in suppression of obesity.

Genetic studies have shown that mutations within the mahogany locus suppress the pleiotropic phenotypes, including obesity, of the agouti-lethal-yellow mutant. Here we identify the mahogany gene and its product; this study, to our knowledge, represents the first positional cloning of a suppressor gene in the mouse. Expression of the mahogany gene is broad; however, in situ hybridization analysis emphasizes the importance of its expression in the ventromedial hypothalamic nucleus, a region that is intimately involved in the regulation of body weight and feeding. We present new genetic studies that indicate that the mahogany locus does not suppress the obese phenotype of the melanocortin-4-receptor null allele or those of the monogenic obese models (Lep(db), tub and Cpe(fat)). However, mahogany can suppress diet-induced obesity, the mechanism of which is likely to have implications for therapeutic intervention in common human obesity. The amino-acid sequence of the mahogany protein suggests that it is a large, single-transmembrane-domain receptor-like molecule, with a short cytoplasmic tail containing a site that is conserved between Caenorhabditis elegans and mammals. We propose two potential, alternative modes of action for mahogany: one draws parallels with the mechanism of action of low-affinity proteoglycan receptors such as fibroblast growth factor and transforming growth factor-beta, and the other suggests that mahogany itself is a signalling receptor.

Nonallelism for the audiogenic seizure prone (Asp1) and the aryl hydrocarbon receptor (Ahr) loci in mice.

Previous studies showed an association between the Ahr locus on Chr 12 and a major gene, Asp1, that influences susceptibility to audiogenic seizures (AGS) in mice. Although the association was thought to involve close linkage, a pleiotropic effect of the Ahr locus on AGS susceptibility was not excluded. Two congenic strains, D2.B6N-Asp1b and the D2N.B6N-Ahrb1, were used to evaluate further the association between the Ahr and Asp1 loci. Both strains are genetically identical to the AGS susceptible DBA/2 (D2) strain except for a small amount of C57BL/6N (B6N) genome surrounding the Ahr locus and encompassing the Asp1 locus. The AGS susceptibility of both congenic strains is similar and significantly lower than that of the D2 strain. We found that the Ahr/Asp1 critical region encompasses 5.5-7.0 cM from the proximal microsatellite marker D12Mit153 to the distal marker D12Mitl12. The D2N.B6N-Ahrb1 expresses B6 alleles for all markers within the critical region, whereas the D2.B6N-Asp1b expresses the B6 allele only at the Asp1 locus. Furthermore, we determined that the D2.B6N-Asp1b mouse expresses both the D2 phenotype and genotype at the Ahr locus, i.e., zoxazolamine paralysis and T to C and G to A transition mutations in the Ahr cDNA at bp sites 3330 and 3336, respectively. We therefore conclude that the Ahr and Asp1 loci are nonallelic and that the Ahr gene is excluded as a candidate for Asp1.