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The glycogen-associated form of protein phosphatase-1 (PP1) derived from skeletal muscle is a heterodimer composed of a 37-kD catalytic subunit (MIM 176875) and a 124-kD targeting and regulatory subunit, referred to as PP1G by Hansen et al. (1995). PP1G binds to muscle glycogen with high affinity, thereby enhancing dephosphorylation of glycogen-bound substrates for PP1 such as glycogen synthase (e.g., MIM 138570) and glycogen phosphorylase kinase (e.g., MIM 306000). Phosphorylation at ser46 of the PP1G subunit in response to insulin increases PP1 activity, while phosphorylation at ser65 in response to adrenaline causes dissociation of the catalytic subunit from the G subunit and inhibits glycogen synthesis. Because of these functions, PP1G was postulated to be involved in noninsulin-dependent diabetes mellitus (NIDDM; MIM 125853) and obesity.[supplied by OMIM] A joint effect between the Asp905 and BMI increases the risk of type 2 diabetes, and Asp905Tyr and ARE polymorphism of PPP1R3 gene are not the major diabetogenic gene variants in Chinese population. Among the largest cohort of nondiabetic subjects (Caucasian, n = 112), the presence of the deletion allele (ARE-2) was associated with insulin resistance and hyperandrogenemia. G(M) promotes glycogen storage and inversely regulates glycogen synthase and glycogen phosphorylase activities, while, specifically, synthase phosphatase activity of G(M)-PP1 is inhibited by glycogen. Inactivation of PPP1R3 gene is associated with tumor progression and metastasis of colorectal cancers. We describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were compound heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A.
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