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Publication
Crucial Role of the SH2B1 PH Domain for the Control of Energy Balance.
Authors Flores A, Argetsinger LS, Stadler LKJ, Malaga AE, Vander PB, DeSantis LC, Joe
RM, Cline JM, Keogh JM, Henning E, Barroso I, Mendes de Oliveira E,
Chandrashekar G, Clutter ES, Hu Y, Stuckey J, Farooqi IS, Myers MG, Carter-Su C
Submitted By Submitted Externally on 2/12/2020
Status Published
Journal Diabetes
Year 2019
Date Published 11/1/2019
Volume : Pages 68 : 2049 - 2062
PubMed Reference 31439647
Abstract Disruption of the adaptor protein SH2B1 (SH2-B, PSM) is associated with severe
obesity, insulin resistance, and neurobehavioral abnormalities in mice and
humans. Here, we identify 15 SH2B1 variants in severely obese children. Four
obesity-associated human SH2B1 variants lie in the Pleckstrin homology (PH)
domain, suggesting that the PH domain is essential for SH2B1's function. We
generated a mouse model of a human variant in this domain (P322S). P322S/P322S
mice exhibited substantial prenatal lethality. Examination of the P322S/+
metabolic phenotype revealed late-onset glucose intolerance. To circumvent
P322S/P322S lethality, mice containing a two-amino acid deletion within the
SH2B1 PH domain (?P317, R318 [?PR]) were studied. Mice homozygous for ?PR were
born at the expected Mendelian ratio and exhibited obesity plus insulin
resistance and glucose intolerance beyond that attributable to their increased
adiposity. These studies demonstrate that the PH domain plays a crucial role in
how SH2B1 controls energy balance and glucose homeostasis.




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