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Submitted on July 1, 2005
Accepted on September 28, 2005
Section on Cellular Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, 20892, USAYerkes National Primate Center of Emory University, Atlanta, GA 30329, USA and Dipartimento di Pediatria, Seconda Universita di Napoli, Via Luigi De Crecchio No.2, 80138, Napoli, Italy
* To whom correspondence should be addressed. 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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