A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice

David B. Savage, Lanmin Zhai, Balasubramanian Ravikumar, Soo Choi Cheol, Johanna E. Snaar, Amanda C. McGuire, Sung Eun Wou, Gemma Medina-Gomez, Sheene Kim, Cheryl B. Bock, Dyann M. Segvich, Antonio Vidal-Puig, Nicholas J. Wareham, Gerald I. Shulman, Fredrik Karpe, Roy Taylor, Bartholomew A. Pederson, Peter J. Roach, Stephen O'Rahilly, Anna A. DePaoli-Roach

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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 RGL, 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 13C 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 C1984DAG (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.

Original languageEnglish (US)
Pages (from-to)113-122
Number of pages10
JournalPLoS Medicine
Volume5
Issue number1
DOIs
StatePublished - Jan 2008

ASJC Scopus subject areas

  • Medicine(all)

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