title: Identification of two novel loss-of-function SIM1 mutations in two overweight children with developmental delay.
abstract: OBJECTIVE
  Several deletions of chromosome 6q, including SIM1, were reported in obese patients with developmental delay. Furthermore, rare loss-of-function SIM1 mutations were shown to contribute to severe obesity, yet the role of these mutations in developmental delay remained unclear. Here, SIM1 in children with neurodevelopmental abnormalities was screened and the functional effect of the identified mutations was investigated.
  
  
  METHODS
  SIM1 was sequenced in 283 children presenting with developmental delay and at least overweight. The effect of the identified mutations on SIM1 transcriptional activity in stable human cell lines was assessed using luciferase gene reporter assays.
  
  
  RESULTS
  Two novel mutations (c.886A>G/p.R296G and c.925A>G/p.S309G) in two boys with variable degrees of cognitive deficits and weight issues were identified. The child mutated for p.R296G presented with a generally more severe phenotype than the p.S309G carrier (obesity, compulsive eating, neonatal hypotonia versus overweight only), while both mutations had strong loss-of-function effects on SIM1 transcriptional activity.
  
  
  CONCLUSIONS
  Severe loss-of-function SIM1 mutations can be associated with a spectrum of developmental delay phenotypes and obesity. Our data suggest that SIM1 sequencing should be performed more systematically in patients with developmental delay, even in the absence of severe obesity. These results deserve further SIM1 screening studies.
authors.affiliation: European Genomic Institute for Diabetes, Lille, France. Correspondence: Philippe Froguel (p.froguel@imperial.ac.uk); CNRS-UMR8199, Lille Pasteur Institute, Lille, France; Lille 2 University, Lille, France; Department of Pediatrics, Saint Antoine Pediatric Hospital, Saint Vincent de Paul Hospital, Catholic University of Lille, Lille, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Montagne
authors.forename: Anne
authors.initials: A
authors.lastname: Raimondo
authors.forename: Bruno
authors.initials: B
authors.lastname: Delobel
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Duban-Bedu
authors.forename: Fanny Stutzmann
authors.initials: FS
authors.lastname: Noblet
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dechaume
authors.forename: David C
authors.initials: DC
authors.lastname: Bersten
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
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics*; D005260:Female; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D009767:Obesity, Morbid / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D008156:Luciferases; D012097:Repressor Proteins; C491094:SIM1 protein, human