201. Human SH2B1 mutations are associated with maladaptive behaviors and obesity.
- Author
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Doche ME, Bochukova EG, Su HW, Pearce LR, Keogh JM, Henning E, Cline JM, Saeed S, Dale A, Cheetham T, Barroso I, Argetsinger LS, O'Rahilly S, Rui L, Carter-Su C, and Farooqi IS
- Subjects
- Adolescent, Adult, Aggression, Base Sequence, Case-Control Studies, Cell Movement, Child, Child, Preschool, DNA Mutational Analysis, Energy Intake genetics, Female, Genetic Association Studies, HEK293 Cells, Humans, Male, Middle Aged, Phenotype, Protein Transport, Social Isolation, Young Adult, Adaptor Proteins, Signal Transducing genetics, Frameshift Mutation, Mutation, Missense, Obesity genetics
- 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.
- Published
- 2012
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