The Leu34Phe ProCART mutation leads to cocaine- and amphetamine-regulated transcript (CART) deficiency: a possible cause for obesity in humans.
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.
Yanik
Tulin
T
Section on Cellular Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4480, USA.
Dominguez
Geraldina
G
Kuhar
Michael J
MJ
Del Giudice
Emanuele M
EM
Loh
Y Peng
YP
D019943:Amino Acid Substitution; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein