Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/79320
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dc.contributor.authorBonnefond, A.en
dc.contributor.authorRaimondo, A.en
dc.contributor.authorStutzmann, F.en
dc.contributor.authorGhoussaini, M.en
dc.contributor.authorRamachandrappa, S.en
dc.contributor.authorBersten, D.en
dc.contributor.authorDurand, E.en
dc.contributor.authorVatin, V.en
dc.contributor.authorBalkau, B.en
dc.contributor.authorLantieri, O.en
dc.contributor.authorRaverdy, V.en
dc.contributor.authorPattou, F.en
dc.contributor.authorVan Hul, W.en
dc.contributor.authorVan Gaal, L.en
dc.contributor.authorPeet, D.en
dc.contributor.authorWeill, J.en
dc.contributor.authorMiller, J.en
dc.contributor.authorHorber, F.en
dc.contributor.authorGoldstone, A.en
dc.contributor.authorDriscoll, D.en
dc.contributor.authoret al.en
dc.date.issued2013en
dc.identifier.citationJournal of Clinical Investigation, 2013; 123(7):3037-3041en
dc.identifier.issn0021-9738en
dc.identifier.issn1558-8238en
dc.identifier.urihttp://hdl.handle.net/2440/79320-
dc.description.abstractSim1 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.en
dc.description.statementofresponsibilityAmélie Bonnefond, Anne Raimondo, Fanny Stutzmann, Maya Ghoussaini, Shwetha Ramachandrappa, David C. Bersten, Emmanuelle Durand, Vincent Vatin, Beverley Balkau, Olivier Lantieri, Violeta Raverdy, François Pattou, Wim Van Hul, Luc Van Gaal, Daniel J. Peet, Jacques Weill, Jennifer L. Miller, Fritz Horber, Anthony P. Goldstone, Daniel J. Driscoll, John B. Bruning, David Meyre, Murray L. Whitelaw and Philippe Froguelen
dc.language.isoenen
dc.publisherAmer Soc Clinical Investigation Incen
dc.rightsCopyright © 2013, American Society for Clinical Investigationen
dc.subjectHumans; Prader-Willi Syndrome; Obesity, Morbid; Luciferases; Repressor Proteins; Case-Control Studies; DNA Mutational Analysis; Gene Expression; Gene Frequency; Mutation, Missense; Genes, Reporter; Models, Molecular; Adult; Middle Aged; Child, Preschool; Infant; Female; Male; Basic Helix-Loop-Helix Transcription Factors; Transcriptional Activation; Young Adult; Genetic Association Studies; HEK293 Cellsen
dc.titleLoss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like featuresen
dc.typeJournal articleen
dc.identifier.rmid0020130372en
dc.identifier.doi10.1172/JCI68035en
dc.identifier.pubid18889-
pubs.library.collectionMolecular and Biomedical Science publicationsen
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
Appears in Collections:Molecular and Biomedical Science publications

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