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- Title
Human SH2B1 mutations are associated with maladaptive behaviors and obesity.
- Authors
Doche, Michael E.; Bochukova, Elena G.; Hsiao-Wen Su; Pearce, Laura R.; Keogh, Julia M.; Henning, Elana; Cline, Joel M.; Dale, Anne; Cheetham, Tim; Barroso, Inês; Argetsinger, Lawrence S.; O'Rahilly, Stephen; Liangyou Rui; Christin Carter-Su; Farooqi, I. Sadaf
- Abstract
Src homology 2 B adapter protein 1 (SH2B1) modulates signaling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, growth hormone (GH), and nerve growth factor (NGF). Targeted deletion of Sh2b1 in mice results in increased food intake, obesity, and insulin resistance, with an intermediate phenotype seen in heterozygous null mice on a high-fat diet. We identified SH2B1 loss-of-function mutations in a large cohort of patients with severe early-onset obesity. Mutation carriers exhibited hyperphagia, childhood-onset obesity, disproportionate insulin resistance, and reduced final height as adults. Unexpectedly, mutation carriers exhibited a spectrum of behavioral abnormalities that were not reported in controls, including social isolation and aggression. We conclude that SH2B1 plays a critical role in the control of human food intake and body weight and is implicated in maladaptive human behavior.
- Subjects
OBESITY; GENETIC mutation; HOMOLOGY (Biology); CELLULAR signal transduction; PROTEIN-tyrosine kinases; LIGANDS (Biochemistry); SOMATOTROPIN; NERVE growth factor
- Publication
Journal of Clinical Investigation, 2012, Vol 122, Issue 12, p4732
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI62696