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...
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| Veröffentlicht in: | Endocrinology (Philadelphia) 2006-01, Vol.147 (1), p.39-43 |
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| creator | Yanik, Tulin Dominguez, Geraldina Kuhar, Michael J Del Giudice, Emanuele M Loh, Y. Peng |
| description | 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. |
| doi_str_mv | 10.1210/en.2005-0812 |
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These results suggest that the obesity observed in humans bearing the Leu34Phe mutation could be due to a putative deficiency in hypothalamic bioactive CART.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2005-0812</identifier><identifier>PMID: 16210370</identifier><identifier>CODEN: ENDOAO</identifier><language>eng</language><publisher>Bethesda, MD: Endocrine Society</publisher><subject>Amino Acid Substitution ; Amphetamines ; Biological activity ; Biological and medical sciences ; Cell Line ; Cocaine ; Cocaine- and amphetamine-regulated transcript protein ; Female ; Fundamental and applied biological sciences. Psychology ; Humans ; Hypothalamus ; Male ; Medical sciences ; Metabolic diseases ; Missense mutation ; Mutagenesis, Site-Directed ; Mutation ; Mutation, Missense ; Nerve Tissue Proteins - blood ; Nerve Tissue Proteins - deficiency ; Nerve Tissue Proteins - genetics ; Neuropharmacology ; Obesity ; Obesity - genetics ; Pharmacology. Drug treatments ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. 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Peng</creatorcontrib><title>The Leu34Phe ProCART Mutation Leads to Cocaine- and Amphetamine-Regulated Transcript (CART) Deficiency: A Possible Cause for Obesity in Humans</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>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.</description><subject>Amino Acid Substitution</subject><subject>Amphetamines</subject><subject>Biological activity</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cocaine</subject><subject>Cocaine- and amphetamine-regulated transcript protein</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Hypothalamus</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Missense mutation</subject><subject>Mutagenesis, Site-Directed</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Nerve Tissue Proteins - blood</subject><subject>Nerve Tissue Proteins - deficiency</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Neuropharmacology</subject><subject>Obesity</subject><subject>Obesity - genetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Recombinant Proteins - metabolism</subject><subject>Transfection</subject><subject>Vertebrates: endocrinology</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kVuL1DAUx4Mo7uzom88SEG9g11yapvVtqJcVRnZYxueSpqduljapSfMwX2I_sykzMCD6lOTkd_7n8kfoBSVXlFHyEewVI0RkpKTsEVrRKheZpJI8RitCKM8kY_ICXYZwn555nvOn6IIWKZNLskIP-zvAW4g836XLzrt6c7vHP-KsZuNs-lFdwLPDtdPKWMiwsh3ejNMdzGpcArfwKw5qhg7vvbJBezPN-N2i8h5_ht5oA1YfPuEN3rkQTDsArlUMgHvn8U0LwcwHbCy-jmNKf4ae9GoI8Px0rtHPr1_29XW2vfn2vd5sMy1EOWcdywvKREdpoQrNJCNVy1tK27YTLSsJVzlnMq_yAkRaS0FFx6FQXJSK9jwnfI3eHHUn735HCHMzmqBhGJQFF0NDK1FVMq1vjV79Bd676G3qreGUEyFTjTJRH46U9mlID30zeTMqf2goaRaXGrDN4lKzuJTwlyfR2I7QneGTLQl4fQJU0Gro02a1CWdO8pJQwRP39si5OP2vZHYqyY8k2M4lkyxMHkI4T_PPRv8AoECzcA</recordid><startdate>200601</startdate><enddate>200601</enddate><creator>Yanik, Tulin</creator><creator>Dominguez, Geraldina</creator><creator>Kuhar, Michael J</creator><creator>Del Giudice, Emanuele M</creator><creator>Loh, Y. 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Psychology</topic><topic>Humans</topic><topic>Hypothalamus</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Missense mutation</topic><topic>Mutagenesis, Site-Directed</topic><topic>Mutation</topic><topic>Mutation, Missense</topic><topic>Nerve Tissue Proteins - blood</topic><topic>Nerve Tissue Proteins - deficiency</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Neuropharmacology</topic><topic>Obesity</topic><topic>Obesity - genetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. 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Peng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Leu34Phe ProCART Mutation Leads to Cocaine- and Amphetamine-Regulated Transcript (CART) Deficiency: A Possible Cause for Obesity in Humans</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2006-01</date><risdate>2006</risdate><volume>147</volume><issue>1</issue><spage>39</spage><epage>43</epage><pages>39-43</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><coden>ENDOAO</coden><abstract>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.</abstract><cop>Bethesda, MD</cop><pub>Endocrine Society</pub><pmid>16210370</pmid><doi>10.1210/en.2005-0812</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Amino Acid Substitution Amphetamines Biological activity Biological and medical sciences Cell Line Cocaine Cocaine- and amphetamine-regulated transcript protein Female Fundamental and applied biological sciences. Psychology Humans Hypothalamus Male Medical sciences Metabolic diseases Missense mutation Mutagenesis, Site-Directed Mutation Mutation, Missense Nerve Tissue Proteins - blood Nerve Tissue Proteins - deficiency Nerve Tissue Proteins - genetics Neuropharmacology Obesity Obesity - genetics Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Recombinant Proteins - metabolism Transfection Vertebrates: endocrinology |
| title | The Leu34Phe ProCART Mutation Leads to Cocaine- and Amphetamine-Regulated Transcript (CART) Deficiency: A Possible Cause for Obesity in Humans |
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