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Endocrinology. 2014 Sep;155(9):3219-26. doi: 10.1210/en.2014-1264. Epub 2014 Jun 27.

Functional characterization of obesity-associated variants involving the α and β isoforms of human SH2B1.

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University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre (L.R.P., J.M.K., E.H., E.G.B., S.G., S.Sa., S.O., I.B., I.S.F.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ United Kingdom; Graduate Program in Cellular and Molecular Biology (R.J., C.C.-S.), Department of Molecular and Integrative Physiology (M.E.D., H.-W.S., L.S.A., J.M.C., L.R., C.C.-S.), and Division of Metabolism, Endocrinology, and Diabetes (C.C.-S.), Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-5622; Joslin Diabetes Center and Department of Medicine (S.Sh.), Harvard University, Boston, Massachusetts 02115; and Wellcome Trust Sanger Institute (I.B.), Hinxton, CB10 1SA United Kingdom.


We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) in individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 variants by sequencing 500 individuals with severe early-onset obesity. SH2B1 has 4 alternatively spliced isoforms. One variant (T546A) lies within the N-terminal region common to all isoforms. As shown for past variants in this region, T546A impairs SH2B1β enhancement of nerve growth factor-induced neurite outgrowth, and the individual with the T546A variant exhibits mild developmental delay. The other 3 variants (A663V, V695M, and A723V) lie in the C-terminal tail of SH2B1α. SH2B1α variant carriers were hyperinsulinemic but did not exhibit the behavioral phenotype observed in individuals with SH2B1 variants that disrupt all isoforms. In in vitro assays, SH2B1α, like SH2B1β, enhances insulin- and leptin-induced insulin receptor substrate 2 (IRS2) phosphorylation and GH-induced cell motility. None of the variants affect SH2B1α enhancement of insulin- and leptin-induced IRS2 phosphorylation. However, T546A, A663V, and A723V all impair the ability of SH2B1α to enhance GH-induced cell motility. In contrast to SH2B1β, SH2B1α does not enhance nerve growth factor-induced neurite outgrowth. These studies suggest that genetic variants that disrupt isoforms other than SH2B1β may be functionally significant. Further studies are needed to understand the mechanism by which the individual isoforms regulate energy homeostasis and behavior.

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