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Introduction The dissection of the genetic basis for interindividual variation in human metabolism is a major goal of contemporary metabolic research. Recently we identified a novel frameshift (FS) premature stop [...], Background Stored glycogen is an important source of energy for skeletal muscle. Human genetic disorders primarily affecting skeletal muscle glycogen turnover are well-recognised, but rare. We previously reported that a frameshift/premature stop mutation in PPP1R3A, the gene encoding [R.sub.GL], a key regulator of muscle glycogen metabolism, was present in 1.36% of participants from a population of white individuals in the UK. However, the functional implications of the mutation were not known. The objective of this study was to characterise the molecular and physiological consequences of this genetic variant. Methods and Findings In this study we found a similar prevalence of the variant in an independent UK white population of 744 participants (1.46%) and, using in vivo [sup.13]C magnetic resonance spectroscopy studies, demonstrate that human carriers (n= 6) of the variant have low basal (65% lower, p = 0.002) and postprandial muscle glycogen levels. Mice engineered to express the equivalent mutation had similarly decreased muscle glycogen levels (40% lower in heterozygous knock-in mice, p < 0.05). In muscle tissue from these mice, failure of the truncated mutant to bind glycogen and colocalize with glycogen synthase (GS) decreased GS and increased glycogen phosphorylase activity states, which account for the decreased glycogen content. Conclusions Thus, PPP1R3A C1984ΔAG (stop codon 668) is, to our knowledge, the first prevalent mutation described that directly impairs glycogen synthesis and decreases glycogen levels in human skeletal muscle. The fact that it is present in ~1 in 70 UK whites increases the potential biomedical relevance of these observations. The Editors' Summary of this article follows the references.

Correction for: Savage DB, Zhai L, Ravikumar B, Choi CS, Snaar JE, et al. (2008) A prevalent variant in PPPIR3A impairs glycogen synthesis and reduces muscle glycogen content in humans [...]

The PPP1R3C gene encoding the protein phosphatase 1 (PP1) glycogen targeting subunit PTG is expressed in insulin sensitive tissues and has been implicated in the insulin control of glycogen metabolism. It has been reported that PTG null mice are not viable and that the heterozygotes develop insulin resistance in an age dependent manner (Crosson, S.M., Khan, A., Printen, J., Pessin, J.E., and Saltiel, A.R. 2003. PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance. J Clin Invest 111:1423-1432). Here we report that two independent lines of PTG null mice generated by our laboratory are viable, are born at the expected frequency for Mendelian inheritance and develop normally. Western immunoblotting of glycogen pellets from skeletal muscle, liver and epididimal fat show that PTG is absent from the null mice and is ∼50% of the wild type in the heterozygotes. Glycogen synthase and PP1 protein levels are unaltered as is the muscle-specific PP1 targeting subunit RGL. Female and male null mice, backcrossed for five generations into the C57B1/6J background, exhibit normal response to glucose tolerance test up to nine months of age, whereas males, but not females, display increased sensitivity to insulin tolerance test. Insulin stimulation of glycogen synthase in skeletal muscle and fat is unaltered. In vivo glucose metabolism analyses by hyperinsulinemic-euglycemic clamps indicate that glucose infusion rates and whole body glucose turnover and glycolysis are increased (P<0.01) in the homozygous as compared to the wild type animals. This increased sensitivity can be accounted for by the increased glucose uptake in skeletal muscle (P<0.05) with no differences in the uptake in brown and white fat, hepatic glucose production, serum insulin and FFA. In addition, the null mice exhibit increased energy expenditure (P<0.05) with normal food consumption and activity. Altogether these results demonstrate that PPP1R3C is not an essential gene and that the absence of PTG results in enhanced whole body insulin sensitivity. [ABSTRACT FROM AUTHOR]