title: Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
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.
authors.affiliation: European Genomic Institute for Diabetes, Lille Pasteur Institute, Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.forename: Anne
authors.initials: A
authors.lastname: Raimondo
authors.forename: Fanny
authors.initials: F
authors.lastname: Stutzmann
authors.forename: Maya
authors.initials: M
authors.lastname: Ghoussaini
authors.forename: Shwetha
authors.initials: S
authors.lastname: Ramachandrappa
authors.forename: David C
authors.initials: DC
authors.lastname: Bersten
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Durand
authors.forename: Vincent
authors.initials: V
authors.lastname: Vatin
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Olivier
authors.initials: O
authors.lastname: Lantieri
authors.forename: Violeta
authors.initials: V
authors.lastname: Raverdy
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
authors.forename: Luc
authors.initials: L
authors.lastname: Van Gaal
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Peet
authors.forename: Jacques
authors.initials: J
authors.lastname: Weill
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Miller
authors.forename: Fritz
authors.initials: F
authors.lastname: Horber
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Goldstone
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Driscoll
authors.forename: John B
authors.initials: JB
authors.lastname: Bruning
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Murray L
authors.initials: ML
authors.lastname: Whitelaw
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D017930:Genes, Reporter; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D009767:Obesity, Morbid / Q000235:genetics*; D011218:Prader-Willi Syndrome / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D008156:Luciferases; D012097:Repressor Proteins; C491094:SIM1 protein, human