title: Rare variants in single-minded 1 (SIM1) are associated with severe obesity.
abstract: Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.
authors.affiliation: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Shwetha
authors.initials: S
authors.lastname: Ramachandrappa
authors.forename: Anne
authors.initials: A
authors.lastname: Raimondo
authors.forename: Anna M G
authors.initials: AM
authors.lastname: Cali
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Elana
authors.initials: E
authors.lastname: Henning
authors.forename: Sadia
authors.initials: S
authors.lastname: Saeed
authors.forename: Amanda
authors.initials: A
authors.lastname: Thompson
authors.forename: Sumedha
authors.initials: S
authors.lastname: Garg
authors.forename: Elena G
authors.initials: EG
authors.lastname: Bochukova
authors.forename: Soren
authors.initials: S
authors.lastname: Brage
authors.forename: Victoria
authors.initials: V
authors.lastname: Trowse
authors.forename: Eleanor
authors.initials: E
authors.lastname: Wheeler
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Sullivan
authors.forename: Mehul
authors.initials: M
authors.lastname: Dattani
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clayton
authors.forename: Vipan
authors.initials: V
authors.lastname: Datta
authors.forename: Vippan
authors.initials: V
authors.lastname: Datta
authors.forename: John B
authors.initials: JB
authors.lastname: Bruning
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Peet
authors.forename: Ines
authors.initials: I
authors.lastname: Barroso
authors.forename: Murray L
authors.initials: ML
authors.lastname: Whitelaw
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
mesh_terms: D000293:Adolescent; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D001827:Body Height / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D007223:Infant; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency; D012097:Repressor Proteins / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D049410:Luciferases, Renilla; D044105:Receptor, Melanocortin, Type 4; D012097:Repressor Proteins; C470072:MC4R protein, human; C491094:SIM1 protein, human