Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/79266
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Type: Journal article
Title: Rare variants in single-minded 1 (SIM1) are associated with severe obesity
Author: Ramachandrappa, S.
Raimondo, A.
Cali, A.
Keogh, J.
Henning, E.
Saeed, S.
Thompson, A.
Garg, S.
Bochukova, E.
Brage, S.
Trowse, V.
Wheeler, E.
Sullivan, A.
Dattani, M.
Clayton, P.
Datta, V.
Bruning, J.
Wareham, N.
O'Rahilly, S.
Peet, D.
et al.
Citation: Journal of Clinical Investigation, 2013; 123(7):3042-3050
Publisher: Amer Soc Clinical Investigation Inc
Issue Date: 2013
ISSN: 0021-9738
1558-8238
Statement of
Responsibility: 
Shwetha Ramachandrappa, Anne Raimondo, Anna M.G. Cali, Julia M. Keough, Elana Henning, Sadia Saeed, Amanda Thompson, Sumedha Garg, Elena G. Bochukova, Soren Brage, Victoria Trowse, Eleanor Wheeler, Adrienne E. Sullivan, Mehul Dattani, Peter E. Clayton, Vippan Datta, John B. Bruning, Nick J. Wareham, Stephen O'Rahilly, Daniel J. Peet, Ines Barroso, Murray L. Whielaw and I. Sadaf Farooqi
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.
Keywords: Humans; Obesity; Luciferases, Renilla; Receptor, Melanocortin, Type 4; Repressor Proteins; Body Height; Case-Control Studies; Pedigree; DNA Mutational Analysis; Gene Expression; Heterozygote; Mutation, Missense; Genes, Reporter; Models, Molecular; Adolescent; Child; Child, Preschool; Infant; Female; Male; Basic Helix-Loop-Helix Transcription Factors; Transcriptional Activation; Genetic Association Studies; HEK293 Cells
Rights: Copyright © 2013, American Society for Clinical Investigation
RMID: 0020130360
DOI: 10.1172/JCI68016
Appears in Collections:Molecular and Biomedical Science publications

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