AustralieFrV1, Main, Exploration, bibRecord, 004616

Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features

Identifieur interne : 004616 ( Main/Exploration ); précédent : 004615; suivant : 004617

Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features

Auteurs : Amélie Bonnefond [France] ; Anne Raimondo [Australie] ; Fanny Stutzmann [France] ; Maya Ghoussaini [France] ; Shwetha Ramachandrappa [Royaume-Uni] ; David C. Bersten [Australie] ; Emmanuelle Durand [France] ; Vincent Vatin [France] ; Beverley Balkau [France] ; Olivier Lantieri [France] ; Violeta Raverdy [France] ; François Pattou [France] ; Wim Van Hul [Belgique] ; Luc Van Gaal [Belgique] ; Daniel J. Peet [Australie] ; Jacques Weill [France] ; Jennifer L. Miller [États-Unis] ; Fritz Horber [Liechtenstein, Suisse] ; Anthony P. Goldstone [États-Unis, Royaume-Uni] ; Daniel J. Driscoll [États-Unis] ; John B. Bruning [Australie] ; David Meyre [France, Canada] ; Murray L. Whitelaw [Australie] ; Philippe Froguel [France, Royaume-Uni]

Source :

The Journal of Clinical Investigation [ 0021-9738 ] ; 2013.

RBID : PMC:3696559

Abstract

Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi–like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 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 SIM1 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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696559

DOI: 10.1172/JCI68035
PubMed: 23778136
PubMed Central: 3696559

Affiliations:

Le document en format XML

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<author><name sortKey="Peet, Daniel J" sort="Peet, Daniel J" uniqKey="Peet D" first="Daniel J." last="Peet">Daniel J. Peet</name>
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<author><name sortKey="Miller, Jennifer L" sort="Miller, Jennifer L" uniqKey="Miller J" first="Jennifer L." last="Miller">Jennifer L. Miller</name>
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<author><name sortKey="Horber, Fritz" sort="Horber, Fritz" uniqKey="Horber F" first="Fritz" last="Horber">Fritz Horber</name>
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<author><name sortKey="Driscoll, Daniel J" sort="Driscoll, Daniel J" uniqKey="Driscoll D" first="Daniel J." last="Driscoll">Daniel J. Driscoll</name>
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<affiliation wicri:level="4"><nlm:aff id="JCI68035">Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.</nlm:aff>
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</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 wicri:level="3"><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>CNRS-UMR8199, Lille Pasteur Institute, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Lille II University, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country>
<wicri:regionArea>Department of Genomics of Common Disease, School of Public Health, Imperial College London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
</titleStmt>
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<idno type="doi">10.1172/JCI68035</idno>
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<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 wicri:level="3"><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>CNRS-UMR8199, Lille Pasteur Institute, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Lille II University, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Raimondo, Anne" sort="Raimondo, Anne" uniqKey="Raimondo A" first="Anne" last="Raimondo">Anne Raimondo</name>
<affiliation wicri:level="1"><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>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide</wicri:regionArea>
<wicri:noRegion>Adelaide</wicri:noRegion>
</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 wicri:level="3"><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>CNRS-UMR8199, Lille Pasteur Institute, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Lille II University, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</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 wicri:level="3"><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>CNRS-UMR8199, Lille Pasteur Institute, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Lille II University, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation><nlm:aff wicri:cut=", and" id="JCI68035">Centre for Cancer Genetic Epidemiology, Department of Oncology</nlm:aff>
<wicri:noCountry code="subfield">Department of Oncology</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ramachandrappa, Shwetha" sort="Ramachandrappa, Shwetha" uniqKey="Ramachandrappa S" first="Shwetha" last="Ramachandrappa">Shwetha Ramachandrappa</name>
<affiliation wicri:level="4"><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>
<country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country>
<wicri:regionArea>Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge, Cambridge</wicri:regionArea>
<orgName type="university">Université de Cambridge</orgName>
<placeName><settlement type="city">Cambridge</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Angleterre de l'Est</region>
</placeName>
</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 wicri:level="1"><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>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide</wicri:regionArea>
<wicri:noRegion>Adelaide</wicri:noRegion>
</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 wicri:level="3"><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>CNRS-UMR8199, Lille Pasteur Institute, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Lille II University, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</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 wicri:level="3"><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>CNRS-UMR8199, Lille Pasteur Institute, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Lille II University, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Balkau, Beverley" sort="Balkau, Beverley" uniqKey="Balkau B" first="Beverley" last="Balkau">Beverley Balkau</name>
<affiliation wicri:level="1"><nlm:aff id="JCI68035">Inserm-U1018, Centre for Research in Epidemiology and Population Health, Villejuif, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Inserm-U1018, Centre for Research in Epidemiology and Population Health, Villejuif</wicri:regionArea>
<wicri:noRegion>Villejuif</wicri:noRegion>
<wicri:noRegion>Villejuif</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="JCI68035">University Paris-Sud, UMRS1018, Villejuif, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>University Paris-Sud, UMRS1018, Villejuif</wicri:regionArea>
<wicri:noRegion>Villejuif</wicri:noRegion>
<wicri:noRegion>Villejuif</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lantieri, Olivier" sort="Lantieri, Olivier" uniqKey="Lantieri O" first="Olivier" last="Lantieri">Olivier Lantieri</name>
<affiliation wicri:level="1"><nlm:aff id="JCI68035">Institut Inter-Régional pour la Santé, La Riche, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Institut Inter-Régional pour la Santé, La Riche</wicri:regionArea>
<wicri:noRegion>La Riche</wicri:noRegion>
<wicri:noRegion>La Riche</wicri:noRegion>
</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 wicri:level="3"><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Lille II University, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Inserm-U859, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Inserm-U859, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</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 wicri:level="3"><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Lille II University, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Inserm-U859, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Inserm-U859, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Endocrine Surgery, Lille University Hospital, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Endocrine Surgery, Lille University Hospital, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</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 wicri:level="4"><nlm:aff id="JCI68035">Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Belgique</country>
<wicri:regionArea>Department of Medical Genetics, University of Antwerp, Antwerp</wicri:regionArea>
<orgName type="university">Université d'Anvers</orgName>
<placeName><settlement type="city">Anvers</settlement>
<region>Région flamande</region>
<region type="district" nuts="2">Province d'Anvers</region>
</placeName>
</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 wicri:level="1"><nlm:aff id="JCI68035">Department of Endocrinology, Antwerp University Hospital, Antwerp, Belgium.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Belgique</country>
<wicri:regionArea>Department of Endocrinology, Antwerp University Hospital, Antwerp</wicri:regionArea>
<wicri:noRegion>Antwerp</wicri:noRegion>
</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 wicri:level="1"><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>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide</wicri:regionArea>
<wicri:noRegion>Adelaide</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Weill, Jacques" sort="Weill, Jacques" uniqKey="Weill J" first="Jacques" last="Weill">Jacques Weill</name>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Pediatric Department, Lille University Hospital, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Pediatric Department, Lille University Hospital, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</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 wicri:level="2"><nlm:aff id="JCI68035">Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida</wicri:regionArea>
<placeName><region type="state">Floride</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Horber, Fritz" sort="Horber, Fritz" uniqKey="Horber F" first="Fritz" last="Horber">Fritz Horber</name>
<affiliation wicri:level="1"><nlm:aff id="JCI68035">Landesspital, Vaduz, Liechtenstein.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Liechtenstein</country>
<wicri:regionArea>Landesspital, Vaduz</wicri:regionArea>
<wicri:noRegion>Vaduz</wicri:noRegion>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">University of Berne, Berne, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
<wicri:regionArea>University of Berne, Berne</wicri:regionArea>
<placeName><settlement type="city">Berne</settlement>
<region type="région" nuts="3">Canton de Berne</region>
</placeName>
</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 wicri:level="2"><nlm:aff id="JCI68035">Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida</wicri:regionArea>
<placeName><region type="state">Floride</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country>
<wicri:regionArea>Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</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 wicri:level="2"><nlm:aff id="JCI68035">Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida</wicri:regionArea>
<placeName><region type="state">Floride</region>
</placeName>
</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 wicri:level="1"><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>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide</wicri:regionArea>
<wicri:noRegion>Adelaide</wicri:noRegion>
</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 wicri:level="3"><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>CNRS-UMR8199, Lille Pasteur Institute, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Lille II University, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="4"><nlm:aff id="JCI68035">Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Canada</country>
<wicri:regionArea>Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario</wicri:regionArea>
<orgName type="university">Université McMaster</orgName>
<placeName><settlement type="city">Hamilton (Ontario)</settlement>
<region type="state">Ontario</region>
</placeName>
</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 wicri:level="1"><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>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide</wicri:regionArea>
<wicri:noRegion>Adelaide</wicri:noRegion>
</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 wicri:level="3"><nlm:aff id="JCI68035">CNRS-UMR8199, Lille Pasteur Institute, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>CNRS-UMR8199, Lille Pasteur Institute, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Lille II University, Lille, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Lille II University, Lille</wicri:regionArea>
<placeName><region type="region">Hauts-de-France</region>
<region type="old region">Nord-Pas-de-Calais</region>
<settlement type="city">Lille</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI68035">Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country>
<wicri:regionArea>Department of Genomics of Common Disease, School of Public Health, Imperial College London, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</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>
<affiliations><list><country><li>Australie</li>
<li>Belgique</li>
<li>Canada</li>
<li>France</li>
<li>Liechtenstein</li>
<li>Royaume-Uni</li>
<li>Suisse</li>
<li>États-Unis</li>
</country>
<region><li>Angleterre</li>
<li>Angleterre de l'Est</li>
<li>Canton de Berne</li>
<li>Floride</li>
<li>Grand Londres</li>
<li>Hauts-de-France</li>
<li>Nord-Pas-de-Calais</li>
<li>Ontario</li>
<li>Province d'Anvers</li>
<li>Région flamande</li>
</region>
<settlement><li>Anvers</li>
<li>Berne</li>
<li>Cambridge</li>
<li>Hamilton (Ontario)</li>
<li>Lille</li>
<li>Londres</li>
</settlement>
<orgName><li>Université McMaster</li>
<li>Université d'Anvers</li>
<li>Université de Cambridge</li>
</orgName>
</list>
<tree><country name="France"><region name="Hauts-de-France"><name sortKey="Bonnefond, Amelie" sort="Bonnefond, Amelie" uniqKey="Bonnefond A" first="Amélie" last="Bonnefond">Amélie Bonnefond</name>
</region>
<name sortKey="Balkau, Beverley" sort="Balkau, Beverley" uniqKey="Balkau B" first="Beverley" last="Balkau">Beverley Balkau</name>
<name sortKey="Balkau, Beverley" sort="Balkau, Beverley" uniqKey="Balkau B" first="Beverley" last="Balkau">Beverley Balkau</name>
<name sortKey="Bonnefond, Amelie" sort="Bonnefond, Amelie" uniqKey="Bonnefond A" first="Amélie" last="Bonnefond">Amélie Bonnefond</name>
<name sortKey="Durand, Emmanuelle" sort="Durand, Emmanuelle" uniqKey="Durand E" first="Emmanuelle" last="Durand">Emmanuelle Durand</name>
<name sortKey="Durand, Emmanuelle" sort="Durand, Emmanuelle" uniqKey="Durand E" first="Emmanuelle" last="Durand">Emmanuelle Durand</name>
<name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name>
<name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name>
<name sortKey="Ghoussaini, Maya" sort="Ghoussaini, Maya" uniqKey="Ghoussaini M" first="Maya" last="Ghoussaini">Maya Ghoussaini</name>
<name sortKey="Ghoussaini, Maya" sort="Ghoussaini, Maya" uniqKey="Ghoussaini M" first="Maya" last="Ghoussaini">Maya Ghoussaini</name>
<name sortKey="Lantieri, Olivier" sort="Lantieri, Olivier" uniqKey="Lantieri O" first="Olivier" last="Lantieri">Olivier Lantieri</name>
<name sortKey="Meyre, David" sort="Meyre, David" uniqKey="Meyre D" first="David" last="Meyre">David Meyre</name>
<name sortKey="Meyre, David" sort="Meyre, David" uniqKey="Meyre D" first="David" last="Meyre">David Meyre</name>
<name sortKey="Pattou, Francois" sort="Pattou, Francois" uniqKey="Pattou F" first="François" last="Pattou">François Pattou</name>
<name sortKey="Pattou, Francois" sort="Pattou, Francois" uniqKey="Pattou F" first="François" last="Pattou">François Pattou</name>
<name sortKey="Pattou, Francois" sort="Pattou, Francois" uniqKey="Pattou F" first="François" last="Pattou">François Pattou</name>
<name sortKey="Raverdy, Violeta" sort="Raverdy, Violeta" uniqKey="Raverdy V" first="Violeta" last="Raverdy">Violeta Raverdy</name>
<name sortKey="Raverdy, Violeta" sort="Raverdy, Violeta" uniqKey="Raverdy V" first="Violeta" last="Raverdy">Violeta Raverdy</name>
<name sortKey="Stutzmann, Fanny" sort="Stutzmann, Fanny" uniqKey="Stutzmann F" first="Fanny" last="Stutzmann">Fanny Stutzmann</name>
<name sortKey="Stutzmann, Fanny" sort="Stutzmann, Fanny" uniqKey="Stutzmann F" first="Fanny" last="Stutzmann">Fanny Stutzmann</name>
<name sortKey="Vatin, Vincent" sort="Vatin, Vincent" uniqKey="Vatin V" first="Vincent" last="Vatin">Vincent Vatin</name>
<name sortKey="Vatin, Vincent" sort="Vatin, Vincent" uniqKey="Vatin V" first="Vincent" last="Vatin">Vincent Vatin</name>
<name sortKey="Weill, Jacques" sort="Weill, Jacques" uniqKey="Weill J" first="Jacques" last="Weill">Jacques Weill</name>
</country>
<country name="Australie"><noRegion><name sortKey="Raimondo, Anne" sort="Raimondo, Anne" uniqKey="Raimondo A" first="Anne" last="Raimondo">Anne Raimondo</name>
</noRegion>
<name sortKey="Bersten, David C" sort="Bersten, David C" uniqKey="Bersten D" first="David C." last="Bersten">David C. Bersten</name>
<name sortKey="Bruning, John B" sort="Bruning, John B" uniqKey="Bruning J" first="John B." last="Bruning">John B. Bruning</name>
<name sortKey="Peet, Daniel J" sort="Peet, Daniel J" uniqKey="Peet D" first="Daniel J." last="Peet">Daniel J. Peet</name>
<name sortKey="Whitelaw, Murray L" sort="Whitelaw, Murray L" uniqKey="Whitelaw M" first="Murray L." last="Whitelaw">Murray L. Whitelaw</name>
</country>
<country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Ramachandrappa, Shwetha" sort="Ramachandrappa, Shwetha" uniqKey="Ramachandrappa S" first="Shwetha" last="Ramachandrappa">Shwetha Ramachandrappa</name>
</region>
<name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name>
<name sortKey="Goldstone, Anthony P" sort="Goldstone, Anthony P" uniqKey="Goldstone A" first="Anthony P." last="Goldstone">Anthony P. Goldstone</name>
</country>
<country name="Belgique"><region name="Région flamande"><name sortKey="Van Hul, Wim" sort="Van Hul, Wim" uniqKey="Van Hul W" first="Wim" last="Van Hul">Wim Van Hul</name>
</region>
<name sortKey="Van Gaal, Luc" sort="Van Gaal, Luc" uniqKey="Van Gaal L" first="Luc" last="Van Gaal">Luc Van Gaal</name>
</country>
<country name="États-Unis"><region name="Floride"><name sortKey="Miller, Jennifer L" sort="Miller, Jennifer L" uniqKey="Miller J" first="Jennifer L." last="Miller">Jennifer L. Miller</name>
</region>
<name sortKey="Driscoll, Daniel J" sort="Driscoll, Daniel J" uniqKey="Driscoll D" first="Daniel J." last="Driscoll">Daniel J. Driscoll</name>
<name sortKey="Goldstone, Anthony P" sort="Goldstone, Anthony P" uniqKey="Goldstone A" first="Anthony P." last="Goldstone">Anthony P. Goldstone</name>
</country>
<country name="Liechtenstein"><noRegion><name sortKey="Horber, Fritz" sort="Horber, Fritz" uniqKey="Horber F" first="Fritz" last="Horber">Fritz Horber</name>
</noRegion>
</country>
<country name="Suisse"><region name="Canton de Berne"><name sortKey="Horber, Fritz" sort="Horber, Fritz" uniqKey="Horber F" first="Fritz" last="Horber">Fritz Horber</name>
</region>
</country>
<country name="Canada"><region name="Ontario"><name sortKey="Meyre, David" sort="Meyre, David" uniqKey="Meyre D" first="David" last="Meyre">David Meyre</name>
</region>
</country>
</tree>
</affiliations>
</record>

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Serveur d'exploration sur les relations entre la France et l'Australie

Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features

Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features

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