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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Loss-of-function mutations in <italic>SIM1</italic> contribute to obesity and Prader-Willi–like features
</title><author><name sortKey="Bonnefond, Amelie" sort="Bonnefond, Amelie" uniqKey="Bonnefond A" first="Amélie" last="Bonnefond">Amélie Bonnefond</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Raimondo, Anne" sort="Raimondo, Anne" uniqKey="Raimondo A" first="Anne" last="Raimondo">Anne Raimondo</name><affiliation><nlm:aff id="JCI68035">School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.</nlm:aff></affiliation></author><author><name sortKey="Stutzmann, Fanny" sort="Stutzmann, Fanny" uniqKey="Stutzmann F" first="Fanny" last="Stutzmann">Fanny Stutzmann</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Ghoussaini, Maya" sort="Ghoussaini, Maya" uniqKey="Ghoussaini M" first="Maya" last="Ghoussaini">Maya Ghoussaini</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="JCI68035">Centre for Cancer Genetic Epidemiology, Department of Oncology</nlm:aff></affiliation></author><author><name sortKey="Ramachandrappa, Shwetha" sort="Ramachandrappa, Shwetha" uniqKey="Ramachandrappa S" first="Shwetha" last="Ramachandrappa">Shwetha Ramachandrappa</name><affiliation><nlm:aff id="JCI68035">Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.</nlm:aff></affiliation></author><author><name sortKey="Bersten, David C" sort="Bersten, David C" uniqKey="Bersten D" first="David C." last="Bersten">David C. Bersten</name><affiliation><nlm:aff id="JCI68035">School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.</nlm:aff></affiliation></author><author><name sortKey="Durand, Emmanuelle" sort="Durand, Emmanuelle" uniqKey="Durand E" first="Emmanuelle" last="Durand">Emmanuelle Durand</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Vatin, Vincent" sort="Vatin, Vincent" uniqKey="Vatin V" first="Vincent" last="Vatin">Vincent Vatin</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Balkau, Beverley" sort="Balkau, Beverley" uniqKey="Balkau B" first="Beverley" last="Balkau">Beverley Balkau</name><affiliation><nlm:aff id="JCI68035">Inserm-U1018, Centre for Research in Epidemiology and Population Health, Villejuif, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">University Paris-Sud, UMRS1018, Villejuif, France.</nlm:aff></affiliation></author><author><name sortKey="Lantieri, Olivier" sort="Lantieri, Olivier" uniqKey="Lantieri O" first="Olivier" last="Lantieri">Olivier Lantieri</name><affiliation><nlm:aff id="JCI68035">Institut Inter-Régional pour la Santé, La Riche, France.</nlm:aff></affiliation></author><author><name sortKey="Raverdy, Violeta" sort="Raverdy, Violeta" uniqKey="Raverdy V" first="Violeta" last="Raverdy">Violeta Raverdy</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Inserm-U859, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Pattou, Francois" sort="Pattou, Francois" uniqKey="Pattou F" first="François" last="Pattou">François Pattou</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Inserm-U859, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Endocrine Surgery, Lille University Hospital, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Van Hul, Wim" sort="Van Hul, Wim" uniqKey="Van Hul W" first="Wim" last="Van Hul">Wim Van Hul</name><affiliation><nlm:aff id="JCI68035">Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Van Gaal, Luc" sort="Van Gaal, Luc" uniqKey="Van Gaal L" first="Luc" last="Van Gaal">Luc Van Gaal</name><affiliation><nlm:aff id="JCI68035">Department of Endocrinology, Antwerp University Hospital, Antwerp, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Peet, Daniel J" sort="Peet, Daniel J" uniqKey="Peet D" first="Daniel J." last="Peet">Daniel J. Peet</name><affiliation><nlm:aff id="JCI68035">School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.</nlm:aff></affiliation></author><author><name sortKey="Weill, Jacques" sort="Weill, Jacques" uniqKey="Weill J" first="Jacques" last="Weill">Jacques Weill</name><affiliation><nlm:aff id="JCI68035">Pediatric Department, Lille University Hospital, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Miller, Jennifer L" sort="Miller, Jennifer L" uniqKey="Miller J" first="Jennifer L." last="Miller">Jennifer L. Miller</name><affiliation><nlm:aff id="JCI68035">Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Horber, Fritz" sort="Horber, Fritz" uniqKey="Horber F" first="Fritz" last="Horber">Fritz Horber</name><affiliation><nlm:aff id="JCI68035">Landesspital, Vaduz, Liechtenstein.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">University of Berne, Berne, Switzerland.</nlm:aff></affiliation></author><author><name sortKey="Goldstone, Anthony P" sort="Goldstone, Anthony P" uniqKey="Goldstone A" first="Anthony P." last="Goldstone">Anthony P. Goldstone</name><affiliation><nlm:aff id="JCI68035">Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom.</nlm:aff></affiliation></author><author><name sortKey="Driscoll, Daniel J" sort="Driscoll, Daniel J" uniqKey="Driscoll D" first="Daniel J." last="Driscoll">Daniel J. Driscoll</name><affiliation><nlm:aff id="JCI68035">Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Bruning, John B" sort="Bruning, John B" uniqKey="Bruning J" first="John B." last="Bruning">John B. Bruning</name><affiliation><nlm:aff id="JCI68035">School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.</nlm:aff></affiliation></author><author><name sortKey="Meyre, David" sort="Meyre, David" uniqKey="Meyre D" first="David" last="Meyre">David Meyre</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.</nlm:aff></affiliation></author><author><name sortKey="Whitelaw, Murray L" sort="Whitelaw, Murray L" uniqKey="Whitelaw M" first="Murray L." last="Whitelaw">Murray L. Whitelaw</name><affiliation><nlm:aff id="JCI68035">School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.</nlm:aff></affiliation></author><author><name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23778136</idno><idno type="pmc">3696559</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696559</idno><idno type="RBID">PMC:3696559</idno><idno type="doi">10.1172/JCI68035</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000198</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000198</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Loss-of-function mutations in <italic>SIM1</italic> contribute to obesity and Prader-Willi–like features
</title><author><name sortKey="Bonnefond, Amelie" sort="Bonnefond, Amelie" uniqKey="Bonnefond A" first="Amélie" last="Bonnefond">Amélie Bonnefond</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Raimondo, Anne" sort="Raimondo, Anne" uniqKey="Raimondo A" first="Anne" last="Raimondo">Anne Raimondo</name><affiliation><nlm:aff id="JCI68035">School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.</nlm:aff></affiliation></author><author><name sortKey="Stutzmann, Fanny" sort="Stutzmann, Fanny" uniqKey="Stutzmann F" first="Fanny" last="Stutzmann">Fanny Stutzmann</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Ghoussaini, Maya" sort="Ghoussaini, Maya" uniqKey="Ghoussaini M" first="Maya" last="Ghoussaini">Maya Ghoussaini</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="JCI68035">Centre for Cancer Genetic Epidemiology, Department of Oncology</nlm:aff></affiliation></author><author><name sortKey="Ramachandrappa, Shwetha" sort="Ramachandrappa, Shwetha" uniqKey="Ramachandrappa S" first="Shwetha" last="Ramachandrappa">Shwetha Ramachandrappa</name><affiliation><nlm:aff id="JCI68035">Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.</nlm:aff></affiliation></author><author><name sortKey="Bersten, David C" sort="Bersten, David C" uniqKey="Bersten D" first="David C." last="Bersten">David C. Bersten</name><affiliation><nlm:aff id="JCI68035">School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.</nlm:aff></affiliation></author><author><name sortKey="Durand, Emmanuelle" sort="Durand, Emmanuelle" uniqKey="Durand E" first="Emmanuelle" last="Durand">Emmanuelle Durand</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Vatin, Vincent" sort="Vatin, Vincent" uniqKey="Vatin V" first="Vincent" last="Vatin">Vincent Vatin</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Balkau, Beverley" sort="Balkau, Beverley" uniqKey="Balkau B" first="Beverley" last="Balkau">Beverley Balkau</name><affiliation><nlm:aff id="JCI68035">Inserm-U1018, Centre for Research in Epidemiology and Population Health, Villejuif, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">University Paris-Sud, UMRS1018, Villejuif, France.</nlm:aff></affiliation></author><author><name sortKey="Lantieri, Olivier" sort="Lantieri, Olivier" uniqKey="Lantieri O" first="Olivier" last="Lantieri">Olivier Lantieri</name><affiliation><nlm:aff id="JCI68035">Institut Inter-Régional pour la Santé, La Riche, France.</nlm:aff></affiliation></author><author><name sortKey="Raverdy, Violeta" sort="Raverdy, Violeta" uniqKey="Raverdy V" first="Violeta" last="Raverdy">Violeta Raverdy</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Inserm-U859, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Pattou, Francois" sort="Pattou, Francois" uniqKey="Pattou F" first="François" last="Pattou">François Pattou</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Inserm-U859, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Endocrine Surgery, Lille University Hospital, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Van Hul, Wim" sort="Van Hul, Wim" uniqKey="Van Hul W" first="Wim" last="Van Hul">Wim Van Hul</name><affiliation><nlm:aff id="JCI68035">Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Van Gaal, Luc" sort="Van Gaal, Luc" uniqKey="Van Gaal L" first="Luc" last="Van Gaal">Luc Van Gaal</name><affiliation><nlm:aff id="JCI68035">Department of Endocrinology, Antwerp University Hospital, Antwerp, Belgium.</nlm:aff></affiliation></author><author><name sortKey="Peet, Daniel J" sort="Peet, Daniel J" uniqKey="Peet D" first="Daniel J." last="Peet">Daniel J. Peet</name><affiliation><nlm:aff id="JCI68035">School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.</nlm:aff></affiliation></author><author><name sortKey="Weill, Jacques" sort="Weill, Jacques" uniqKey="Weill J" first="Jacques" last="Weill">Jacques Weill</name><affiliation><nlm:aff id="JCI68035">Pediatric Department, Lille University Hospital, Lille, France.</nlm:aff></affiliation></author><author><name sortKey="Miller, Jennifer L" sort="Miller, Jennifer L" uniqKey="Miller J" first="Jennifer L." last="Miller">Jennifer L. Miller</name><affiliation><nlm:aff id="JCI68035">Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Horber, Fritz" sort="Horber, Fritz" uniqKey="Horber F" first="Fritz" last="Horber">Fritz Horber</name><affiliation><nlm:aff id="JCI68035">Landesspital, Vaduz, Liechtenstein.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">University of Berne, Berne, Switzerland.</nlm:aff></affiliation></author><author><name sortKey="Goldstone, Anthony P" sort="Goldstone, Anthony P" uniqKey="Goldstone A" first="Anthony P." last="Goldstone">Anthony P. Goldstone</name><affiliation><nlm:aff id="JCI68035">Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom.</nlm:aff></affiliation></author><author><name sortKey="Driscoll, Daniel J" sort="Driscoll, Daniel J" uniqKey="Driscoll D" first="Daniel J." last="Driscoll">Daniel J. Driscoll</name><affiliation><nlm:aff id="JCI68035">Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA.</nlm:aff></affiliation></author><author><name sortKey="Bruning, John B" sort="Bruning, John B" uniqKey="Bruning J" first="John B." last="Bruning">John B. Bruning</name><affiliation><nlm:aff id="JCI68035">School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.</nlm:aff></affiliation></author><author><name sortKey="Meyre, David" sort="Meyre, David" uniqKey="Meyre D" first="David" last="Meyre">David Meyre</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.</nlm:aff></affiliation></author><author><name sortKey="Whitelaw, Murray L" sort="Whitelaw, Murray L" uniqKey="Whitelaw M" first="Murray L." last="Whitelaw">Murray L. Whitelaw</name><affiliation><nlm:aff id="JCI68035">School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.</nlm:aff></affiliation></author><author><name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name><affiliation><nlm:aff wicri:cut=" and" id="JCI68035">European Genomic Institute for Diabetes</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff></affiliation><affiliation><nlm:aff id="JCI68035">Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.</nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><idno type="eISSN">1558-8238</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><italic>Sim1</italic> haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes <italic>SIM1</italic>, were reported in obese children with a Prader-Willi–like syndrome; however, <italic>SIM1</italic> involvement in obesity has never been conclusively demonstrated. Here, <italic>SIM1</italic> was sequenced in 44 children with Prader-Willi–like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi–like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers’ relatives, we found a significant contribution of <italic>SIM1</italic> rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi–like features.
</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Invest</journal-id><journal-id journal-id-type="iso-abbrev">J. Clin. Invest</journal-id><journal-id journal-id-type="publisher-id">J CLIN INVEST</journal-id><journal-title-group><journal-title>The Journal of Clinical Investigation</journal-title></journal-title-group><issn pub-type="ppub">0021-9738</issn><issn pub-type="epub">1558-8238</issn><publisher><publisher-name>American Society for Clinical Investigation</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23778136</article-id><article-id pub-id-type="pmc">3696559</article-id><article-id pub-id-type="publisher-id">68035</article-id><article-id pub-id-type="doi">10.1172/JCI68035</article-id><article-categories><subj-group subj-group-type="heading"><subject>Brief Report</subject></subj-group></article-categories><title-group><article-title>Loss-of-function mutations in <italic>SIM1</italic> contribute to obesity and Prader-Willi–like features
</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Bonnefond</surname><given-names>Amélie</given-names></name><xref ref-type="aff" rid="JCI68035">1</xref><xref ref-type="aff" rid="JCI68035">2</xref><xref ref-type="aff" rid="JCI68035">3</xref></contrib><contrib contrib-type="author"><name><surname>Raimondo</surname><given-names>Anne</given-names></name><xref ref-type="aff" rid="JCI68035">4</xref></contrib><contrib contrib-type="author"><name><surname>Stutzmann</surname><given-names>Fanny</given-names></name><xref ref-type="aff" rid="JCI68035">1</xref><xref ref-type="aff" rid="JCI68035">2</xref><xref ref-type="aff" rid="JCI68035">3</xref></contrib><contrib contrib-type="author"><name><surname>Ghoussaini</surname><given-names>Maya</given-names></name><xref ref-type="aff" rid="JCI68035">1</xref><xref ref-type="aff" rid="JCI68035">2</xref><xref ref-type="aff" rid="JCI68035">3</xref><xref ref-type="aff" rid="JCI68035">5</xref></contrib><contrib contrib-type="author"><name><surname>Ramachandrappa</surname><given-names>Shwetha</given-names></name><xref ref-type="aff" rid="JCI68035">6</xref></contrib><contrib contrib-type="author"><name><surname>Bersten</surname><given-names>David C.</given-names></name><xref ref-type="aff" rid="JCI68035">4</xref></contrib><contrib contrib-type="author"><name><surname>Durand</surname><given-names>Emmanuelle</given-names></name><xref ref-type="aff" rid="JCI68035">1</xref><xref ref-type="aff" rid="JCI68035">2</xref><xref ref-type="aff" rid="JCI68035">3</xref></contrib><contrib contrib-type="author"><name><surname>Vatin</surname><given-names>Vincent</given-names></name><xref ref-type="aff" rid="JCI68035">1</xref><xref ref-type="aff" rid="JCI68035">2</xref><xref ref-type="aff" rid="JCI68035">3</xref></contrib><contrib contrib-type="author"><name><surname>Balkau</surname><given-names>Beverley</given-names></name><xref ref-type="aff" rid="JCI68035">7</xref><xref ref-type="aff" rid="JCI68035">8</xref></contrib><contrib contrib-type="author"><name><surname>Lantieri</surname><given-names>Olivier</given-names></name><xref ref-type="aff" rid="JCI68035">9</xref></contrib><contrib contrib-type="author"><name><surname>Raverdy</surname><given-names>Violeta</given-names></name><xref ref-type="aff" rid="JCI68035">1</xref><xref ref-type="aff" rid="JCI68035">3</xref><xref ref-type="aff" rid="JCI68035">10</xref></contrib><contrib contrib-type="author"><name><surname>Pattou</surname><given-names>François</given-names></name><xref ref-type="aff" rid="JCI68035">1</xref><xref ref-type="aff" rid="JCI68035">3</xref><xref ref-type="aff" rid="JCI68035">10</xref><xref ref-type="aff" rid="JCI68035">11</xref></contrib><contrib contrib-type="author"><name><surname>Van Hul</surname><given-names>Wim</given-names></name><xref ref-type="aff" rid="JCI68035">12</xref></contrib><contrib contrib-type="author"><name><surname>Van Gaal</surname><given-names>Luc</given-names></name><xref ref-type="aff" rid="JCI68035">13</xref></contrib><contrib contrib-type="author"><name><surname>Peet</surname><given-names>Daniel J.</given-names></name><xref ref-type="aff" rid="JCI68035">4</xref></contrib><contrib contrib-type="author"><name><surname>Weill</surname><given-names>Jacques</given-names></name><xref ref-type="aff" rid="JCI68035">14</xref></contrib><contrib contrib-type="author"><name><surname>Miller</surname><given-names>Jennifer L.</given-names></name><xref ref-type="aff" rid="JCI68035">15</xref></contrib><contrib contrib-type="author"><name><surname>Horber</surname><given-names>Fritz</given-names></name><xref ref-type="aff" rid="JCI68035">16</xref><xref ref-type="aff" rid="JCI68035">17</xref></contrib><contrib contrib-type="author"><name><surname>Goldstone</surname><given-names>Anthony P.</given-names></name><xref ref-type="aff" rid="JCI68035">15</xref><xref ref-type="aff" rid="JCI68035">18</xref></contrib><contrib contrib-type="author"><name><surname>Driscoll</surname><given-names>Daniel J.</given-names></name><xref ref-type="aff" rid="JCI68035">15</xref></contrib><contrib contrib-type="author"><name><surname>Bruning</surname><given-names>John B.</given-names></name><xref ref-type="aff" rid="JCI68035">4</xref></contrib><contrib contrib-type="author"><name><surname>Meyre</surname><given-names>David</given-names></name><xref ref-type="aff" rid="JCI68035">1</xref><xref ref-type="aff" rid="JCI68035">2</xref><xref ref-type="aff" rid="JCI68035">3</xref><xref ref-type="aff" rid="JCI68035">19</xref></contrib><contrib contrib-type="author"><name><surname>Whitelaw</surname><given-names>Murray L.</given-names></name><xref ref-type="aff" rid="JCI68035">4</xref></contrib><contrib contrib-type="author"><name><surname>Froguel</surname><given-names>Philippe</given-names></name><xref ref-type="aff" rid="JCI68035">1</xref><xref ref-type="aff" rid="JCI68035">2</xref><xref ref-type="aff" rid="JCI68035">3</xref><xref ref-type="aff" rid="JCI68035">20</xref></contrib></contrib-group><aff id="JCI68035"><label>1</label>European Genomic Institute for Diabetes and<label>2</label>CNRS-UMR8199, Lille Pasteur Institute, Lille, France.<label>3</label>Lille II University, Lille, France.<label>4</label>School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, Australia.<label>5</label>Centre for Cancer Genetic Epidemiology, Department of Oncology, and<label>6</label>Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.<label>7</label>Inserm-U1018, Centre for Research in Epidemiology and Population Health, Villejuif, France.<label>8</label>University Paris-Sud, UMRS1018, Villejuif, France.<label>9</label>Institut Inter-Régional pour la Santé, La Riche, France.<label>10</label>Inserm-U859, Lille, France.<label>11</label>Endocrine Surgery, Lille University Hospital, Lille, France.<label>12</label>Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.<label>13</label>Department of Endocrinology, Antwerp University Hospital, Antwerp, Belgium.<label>14</label>Pediatric Department, Lille University Hospital, Lille, France.<label>15</label>Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA.<label>16</label>Landesspital, Vaduz, Liechtenstein.<label>17</label>University of Berne, Berne, Switzerland.<label>18</label>Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom.<label>19</label>Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.<label>20</label>Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.</aff><author-notes><corresp>Address correspondence to: Philippe Froguel, 1, rue du Prof Calmette BP245, 59019 Lille Cedex, France. Phone: 33.0.3.2087.7911; Fax: 33.0.3.2087.7229; E-mail:
<email>p.froguel@imperial.ac.uk</email>. Or to: Murray L. Whitelaw, School of Molecular and Biomedical Science, University of Adelaide, 5005 Adelaide, Australia. Phone: 61.0.8.8303.4724; Fax: 61.0.8.8313.4362; E-mail:
<email>murray.whitelaw@adelaide.edu.au</email>. Or to: David Meyre, Department of Clinical Epidemiology and Biostatistics, Michael DeGroote Centre for Learning and Discovery, Room 3205, 1280 Main Street West, Hamilton, L8S4L8 Ontario, Canada. Phone: 905.527.4322; Fax: 905.525.9140; E-mail:
<email>meyred@mcmaster.ca</email>.
</corresp><fn><p><bold>Authorship note:</bold> Amélie Bonnefond, Anne Raimondo, and Fanny Stutzmann contributed equally to this work.
</p></fn></author-notes><pub-date pub-type="epub"><day>17</day><month>6</month><year>2013</year></pub-date><pub-date pub-type="ppub"><day>1</day><month>7</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>17</day><month>6</month><year>2013</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>123</volume><issue>7</issue><fpage>3037</fpage><lpage>3041</lpage><history><date date-type="received"><day>27</day><month>11</month><year>2012</year></date><date date-type="accepted"><day>18</day><month>4</month><year>2013</year></date></history><permissions><copyright-statement>Copyright © 2013, American Society for Clinical Investigation</copyright-statement><copyright-year>2013</copyright-year></permissions><abstract><p><italic>Sim1</italic> haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes <italic>SIM1</italic>, were reported in obese children with a Prader-Willi–like syndrome; however, <italic>SIM1</italic> involvement in obesity has never been conclusively demonstrated. Here, <italic>SIM1</italic> was sequenced in 44 children with Prader-Willi–like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi–like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers’ relatives, we found a significant contribution of <italic>SIM1</italic> rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi–like features.
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