Poor Cell Surface Expression of Human Melanocortin-4 Receptor Mutations Associated with Obesity
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of body weight in rodents. Mutations in the coding region of the MC4R are found more frequently in obese individuals, supporting the hypothesis that also in humans deficient melanocortin signaling may lead to obesity. Famil...
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| Veröffentlicht in: | The Journal of biological chemistry 2003-06, Vol.278 (25), p.22939-22945 |
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| creator | Nijenhuis, Wouter A J Garner, Keith M van Rozen, Rea J Adan, Roger A H |
| description | The melanocortin-4 receptor (MC4R) plays an important role in the regulation of body weight in rodents. Mutations in the
coding region of the MC4R are found more frequently in obese individuals, supporting the hypothesis that also in humans
deficient melanocortin signaling may lead to obesity. Family studies that were carried out to demonstrate the relevance of
single mutations for obesity were mostly inconclusive, most likely due to small sample size and complexity of the trait.
In addition, the existing pharmacological data of the mutant receptors are limited in that for most mutations the effect
on receptor expression level and Agouti-related protein (AgRP) pharmacology have not been studied. The aim of the present
study was to gain further insight into the impact of the MC4R mutations on receptor function. Eleven missense mutations
were tested for cell surface expression, affinity for α-melanocyte-stimulating hormone (α-MSH) and AgRP-(83â132), and the
biological response to α-MSH. All mutants were poorly expressed at the cell surface, as measured by 125 I-[Nle 4 - D -Phe 7 ]α-MSH binding, and only a few mutants showed altered pharmacology for α-MSH and AgRP. Hemagglutinin-tagged mutant receptors
were retained in the intracellular environment. These pharmacological data provide a basis to estimate the quantitative
effect of MC4R mutations for the development of obesity. |
| doi_str_mv | 10.1074/jbc.M211326200 |
| format | Article |
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coding region of the MC4R are found more frequently in obese individuals, supporting the hypothesis that also in humans
deficient melanocortin signaling may lead to obesity. Family studies that were carried out to demonstrate the relevance of
single mutations for obesity were mostly inconclusive, most likely due to small sample size and complexity of the trait.
In addition, the existing pharmacological data of the mutant receptors are limited in that for most mutations the effect
on receptor expression level and Agouti-related protein (AgRP) pharmacology have not been studied. The aim of the present
study was to gain further insight into the impact of the MC4R mutations on receptor function. Eleven missense mutations
were tested for cell surface expression, affinity for α-melanocyte-stimulating hormone (α-MSH) and AgRP-(83â132), and the
biological response to α-MSH. All mutants were poorly expressed at the cell surface, as measured by 125 I-[Nle 4 - D -Phe 7 ]α-MSH binding, and only a few mutants showed altered pharmacology for α-MSH and AgRP. Hemagglutinin-tagged mutant receptors
were retained in the intracellular environment. These pharmacological data provide a basis to estimate the quantitative
effect of MC4R mutations for the development of obesity.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M211326200</identifier><identifier>PMID: 12690102</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Amino Acid Substitution ; Animals ; Base Sequence ; Body Weight ; Codon, Nonsense - genetics ; DNA Primers ; Frameshift Mutation ; Gene Expression Regulation ; Humans ; Mutation ; Mutation, Missense ; Obesity - genetics ; Receptor, Melanocortin, Type 4 ; Receptors, Corticotropin - genetics ; Receptors, Corticotropin - metabolism</subject><ispartof>The Journal of biological chemistry, 2003-06, Vol.278 (25), p.22939-22945</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-463e1206bd62ed3a26d40125995095be7e262260bdec66e10f6d20ef24732c493</citedby><cites>FETCH-LOGICAL-c391t-463e1206bd62ed3a26d40125995095be7e262260bdec66e10f6d20ef24732c493</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12690102$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nijenhuis, Wouter A J</creatorcontrib><creatorcontrib>Garner, Keith M</creatorcontrib><creatorcontrib>van Rozen, Rea J</creatorcontrib><creatorcontrib>Adan, Roger A H</creatorcontrib><title>Poor Cell Surface Expression of Human Melanocortin-4 Receptor Mutations Associated with Obesity</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The melanocortin-4 receptor (MC4R) plays an important role in the regulation of body weight in rodents. Mutations in the
coding region of the MC4R are found more frequently in obese individuals, supporting the hypothesis that also in humans
deficient melanocortin signaling may lead to obesity. Family studies that were carried out to demonstrate the relevance of
single mutations for obesity were mostly inconclusive, most likely due to small sample size and complexity of the trait.
In addition, the existing pharmacological data of the mutant receptors are limited in that for most mutations the effect
on receptor expression level and Agouti-related protein (AgRP) pharmacology have not been studied. The aim of the present
study was to gain further insight into the impact of the MC4R mutations on receptor function. Eleven missense mutations
were tested for cell surface expression, affinity for α-melanocyte-stimulating hormone (α-MSH) and AgRP-(83â132), and the
biological response to α-MSH. All mutants were poorly expressed at the cell surface, as measured by 125 I-[Nle 4 - D -Phe 7 ]α-MSH binding, and only a few mutants showed altered pharmacology for α-MSH and AgRP. Hemagglutinin-tagged mutant receptors
were retained in the intracellular environment. These pharmacological data provide a basis to estimate the quantitative
effect of MC4R mutations for the development of obesity.</description><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Body Weight</subject><subject>Codon, Nonsense - genetics</subject><subject>DNA Primers</subject><subject>Frameshift Mutation</subject><subject>Gene Expression Regulation</subject><subject>Humans</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Obesity - genetics</subject><subject>Receptor, Melanocortin, Type 4</subject><subject>Receptors, Corticotropin - genetics</subject><subject>Receptors, Corticotropin - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEFv1DAQhS0EokvLlSPyAXHLMh4nTnysVqVF6qoIqMTNcpwJ62oTL7aj0n9fo12pc5nL9570PsY-CFgLaOsvD71bb1EIiQoBXrGVgE5WshG_X7MVAIpKY9OdsXcpPUC5Wou37Eyg0iAAV8x8DyHyDe33_OcSR-uIX_07RErJh5mHkd8sk535lvZ2Di7E7Oeq5j_I0SGX4HbJNhcy8cuUgvM208Affd7xu56Sz08X7M1o94nen_45u_969WtzU93eXX_bXN5WTmqRq1pJEgiqHxTSIC2qoQaBjdYN6Kanlso-VNAP5JQiAaMaEGjEupXoai3P2edj7yGGvwulbCafXJllZwpLMqJrO1V3TQHXR9DFkFKk0Ryin2x8MgLMf6WmKDUvSkvg46l56ScaXvCTwwJ8OgI7_2f36COZ3ge3o8lg2xlsDKKWWj4D9tp9SA</recordid><startdate>20030620</startdate><enddate>20030620</enddate><creator>Nijenhuis, Wouter A J</creator><creator>Garner, Keith M</creator><creator>van Rozen, Rea J</creator><creator>Adan, Roger A H</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20030620</creationdate><title>Poor Cell Surface Expression of Human Melanocortin-4 Receptor Mutations Associated with Obesity</title><author>Nijenhuis, Wouter A J ; Garner, Keith M ; van Rozen, Rea J ; Adan, Roger A H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-463e1206bd62ed3a26d40125995095be7e262260bdec66e10f6d20ef24732c493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Body Weight</topic><topic>Codon, Nonsense - genetics</topic><topic>DNA Primers</topic><topic>Frameshift Mutation</topic><topic>Gene Expression Regulation</topic><topic>Humans</topic><topic>Mutation</topic><topic>Mutation, Missense</topic><topic>Obesity - genetics</topic><topic>Receptor, Melanocortin, Type 4</topic><topic>Receptors, Corticotropin - genetics</topic><topic>Receptors, Corticotropin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nijenhuis, Wouter A J</creatorcontrib><creatorcontrib>Garner, Keith M</creatorcontrib><creatorcontrib>van Rozen, Rea J</creatorcontrib><creatorcontrib>Adan, Roger A H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nijenhuis, Wouter A J</au><au>Garner, Keith M</au><au>van Rozen, Rea J</au><au>Adan, Roger A H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Poor Cell Surface Expression of Human Melanocortin-4 Receptor Mutations Associated with Obesity</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2003-06-20</date><risdate>2003</risdate><volume>278</volume><issue>25</issue><spage>22939</spage><epage>22945</epage><pages>22939-22945</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The melanocortin-4 receptor (MC4R) plays an important role in the regulation of body weight in rodents. Mutations in the
coding region of the MC4R are found more frequently in obese individuals, supporting the hypothesis that also in humans
deficient melanocortin signaling may lead to obesity. Family studies that were carried out to demonstrate the relevance of
single mutations for obesity were mostly inconclusive, most likely due to small sample size and complexity of the trait.
In addition, the existing pharmacological data of the mutant receptors are limited in that for most mutations the effect
on receptor expression level and Agouti-related protein (AgRP) pharmacology have not been studied. The aim of the present
study was to gain further insight into the impact of the MC4R mutations on receptor function. Eleven missense mutations
were tested for cell surface expression, affinity for α-melanocyte-stimulating hormone (α-MSH) and AgRP-(83â132), and the
biological response to α-MSH. All mutants were poorly expressed at the cell surface, as measured by 125 I-[Nle 4 - D -Phe 7 ]α-MSH binding, and only a few mutants showed altered pharmacology for α-MSH and AgRP. Hemagglutinin-tagged mutant receptors
were retained in the intracellular environment. These pharmacological data provide a basis to estimate the quantitative
effect of MC4R mutations for the development of obesity.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>12690102</pmid><doi>10.1074/jbc.M211326200</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2003-06, Vol.278 (25), p.22939-22945 |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Amino Acid Substitution Animals Base Sequence Body Weight Codon, Nonsense - genetics DNA Primers Frameshift Mutation Gene Expression Regulation Humans Mutation Mutation, Missense Obesity - genetics Receptor, Melanocortin, Type 4 Receptors, Corticotropin - genetics Receptors, Corticotropin - metabolism |
| title | Poor Cell Surface Expression of Human Melanocortin-4 Receptor Mutations Associated with Obesity |
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