The mouse mahogany locus encodes a transmembrane form of human attractin

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Abstract

Agouti protein and agouti-related protein are homologous paracrine signalling molecules that normally regulate hair colour and body weight, respectively, by antagonizing signalling through melanocortin receptors1,2,3,4,5,6,7. Expression of Agouti is normally limited to the skin, but rare alleles from which Agouti is expressed ubiquitously, such as lethal yellow, have pleiotropic effects that include a yellow coat, obesity, increased linear growth, and immune defects8,9,10,11. The mahogany (mg) mutation suppresses the effects of lethal yellow on pigmentation and body weight, and results of our previous genetic studies place mg downstream of transcription of Agouti but upstream of melanocortin receptors12. Here we use positional cloning to identify a candidate gene for mahogany, Mgca. The predicted protein encoded by Mgca is a 1,428-amino-acid, single-transmembrane-domain protein that is expressed in many tissues, including pigment cells and the hypothalamus. The extracellular domain of the Mgca protein is the orthologue of human attractin, a circulating molecule produced by activated T cells that has been implicated in immune-cell interactions13,14. These observations provide new insight into the regulation of energy metabolism and indicate a molecular basis for crosstalk between melanocortin-receptor signalling and immune function.

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Figure 1: Expression of Mgca in wild-type and mg mutant mice.
Figure 2: Genetic and physical map of the mg 3J candidate interval.
Figure 3: Predicted protein sequence of Mgca and location of mahogany mutations.
Figure 4: Effect of mg on Agouti protein and potential mechanisms of action of mahogany.

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Acknowledgements

We thank J. Westerman for providing mg L/mg L mice; R. Mukherjee for technical assistance; S. Kalman and J. Kerns for help with sequence assembly and agouti protein studies, respectively; A. Zuberi for communicating the results of genetic mapping studies before publication; and H. Sweet for information about the origin of mg 3J. This work was supported by grants to G.S.B., S.F.S. and R.W.D. from the NIH, and by an American Heart Association Western States fellowship award to T.M.G. G.S.B. is an Associate Investigator of the Howard Hughes Medical Institute.

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Correspondence to Gregory S. Barsh.

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