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

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  • 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.


  • Bonnefond, Amélie
  • Raimondo, Anne
  • Stutzmann, Fanny
  • Ghoussaini, Maya
  • Ramachandrappa, Shwetha
  • Bersten, David C
  • Durand, Emmanuelle
  • Vatin, Vincent
  • Balkau, Beverley
  • Lantieri, Olivier
  • Raverdy, Violeta
  • Pattou, François
  • Van Hul, Wim
  • Van Gaal, Luc
  • Peet, Daniel J
  • Weill, Jacques
  • Miller, Jennifer L
  • Horber, Fritz
  • Goldstone, Anthony P
  • Driscoll, Daniel J
  • Bruning, John B
  • Meyre, David Jean-Claude
  • Whitelaw, Murray L
  • Froguel, Philippe

publication date

  • July 1, 2013

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