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The Leu34Phe ProCART Mutation Leads to Cocaine- and Amphetamine-Regulated Transcript (CART) Deficiency: A Possible Cause for Obesity in Humans

Section on Cellular Neurobiology (T.Y., Y.P.L.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Yerkes National Primate Center of Emory University (G.D., M.J.K.), Atlanta, Georgia 30329; and Dipartimento di Pediatria (E.M.D.G.), Seconda Universita di Napoli, 80138 Napoli, Italy

Address all correspondence and requests for reprints to: Dr. Y. Peng Loh, Section on Cellular Neurobiology, Building 49, Room 5A22, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4480. E-mail: lohp{at}mail.nih.gov.

Cocaine- and amphetamine-regulated transcript (CART) is an anorexigenic neuropeptide synthesized in the hypothalamus. A Leu34Phe missense mutation in proCART has been found in an obese family in humans. Here we show that humans bearing the Leu34Phe mutation in proCART have severely diminished levels of bioactive CART, but elevated amounts of partially processed proCART in their serum. Expression of wild-type proCART in AtT-20 cells showed that it was sorted to the regulated secretory pathway, a necessity for proper processing to bioactive CART. However, expressed Leu34Phe proCART was missorted, poorly processed, and secreted constitutively. The defective intracellular sorting of Leu34Phe proCART would account for the reduced levels of bioactive CART in affected humans. These results suggest that the obesity observed in humans bearing the Leu34Phe mutation could be due to a putative deficiency in hypothalamic bioactive CART.

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