A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice.
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 mu...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2008-01-01
|
| Series: | PLoS Medicine |
| Online Access: | http://europepmc.org/articles/PMC2214798 |
| _version_ | 1828894481696423936 |
|---|---|
| author | David B Savage Lanmin Zhai Balasubramanian Ravikumar Cheol Soo Choi Johanna E Snaar Amanda C McGuire Sung-Eun Wou Gemma Medina-Gomez Sheene Kim Cheryl B Bock Dyann M Segvich Bhavana Solanky Dinesh Deelchand 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 |
| author_facet | David B Savage Lanmin Zhai Balasubramanian Ravikumar Cheol Soo Choi Johanna E Snaar Amanda C McGuire Sung-Eun Wou Gemma Medina-Gomez Sheene Kim Cheryl B Bock Dyann M Segvich Bhavana Solanky Dinesh Deelchand 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 |
| author_sort | David B Savage |
| collection | DOAJ |
| description | 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.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 (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.Thus, PPP1R3A C1984DeltaAG (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 approximately 1 in 70 UK whites increases the potential biomedical relevance of these observations. |
| first_indexed | 2024-12-13T14:12:14Z |
| format | Article |
| id | doaj.art-6ce03d253c6846a6a8db7e41f2d27e2d |
| institution | Directory Open Access Journal |
| issn | 1549-1277 1549-1676 |
| language | English |
| last_indexed | 2024-12-13T14:12:14Z |
| publishDate | 2008-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Medicine |
| spelling | doaj.art-6ce03d253c6846a6a8db7e41f2d27e2d2022-12-21T23:42:26ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762008-01-0151e2710.1371/journal.pmed.0050027A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice.David B SavageLanmin ZhaiBalasubramanian RavikumarCheol Soo ChoiJohanna E SnaarAmanda C McGuireSung-Eun WouGemma Medina-GomezSheene KimCheryl B BockDyann M SegvichBhavana SolankyDinesh DeelchandAntonio Vidal-PuigNicholas J WarehamGerald I ShulmanFredrik KarpeRoy TaylorBartholomew A PedersonPeter J RoachStephen O'RahillyAnna A DePaoli-RoachStored 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.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 (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.Thus, PPP1R3A C1984DeltaAG (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 approximately 1 in 70 UK whites increases the potential biomedical relevance of these observations.http://europepmc.org/articles/PMC2214798 |
| spellingShingle | David B Savage Lanmin Zhai Balasubramanian Ravikumar Cheol Soo Choi Johanna E Snaar Amanda C McGuire Sung-Eun Wou Gemma Medina-Gomez Sheene Kim Cheryl B Bock Dyann M Segvich Bhavana Solanky Dinesh Deelchand 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 A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. PLoS Medicine |
| title | A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. |
| title_full | A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. |
| title_fullStr | A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. |
| title_full_unstemmed | A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. |
| title_short | A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. |
| title_sort | prevalent variant in ppp1r3a impairs glycogen synthesis and reduces muscle glycogen content in humans and mice |
| url | http://europepmc.org/articles/PMC2214798 |
| work_keys_str_mv | AT davidbsavage aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT lanminzhai aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT balasubramanianravikumar aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT cheolsoochoi aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT johannaesnaar aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT amandacmcguire aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT sungeunwou aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT gemmamedinagomez aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT sheenekim aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT cherylbbock aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT dyannmsegvich aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT bhavanasolanky aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT dineshdeelchand aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT antoniovidalpuig aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT nicholasjwareham aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT geraldishulman aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT fredrikkarpe aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT roytaylor aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT bartholomewapederson aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT peterjroach aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT stephenorahilly aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT annaadepaoliroach aprevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT davidbsavage prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT lanminzhai prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT balasubramanianravikumar prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT cheolsoochoi prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT johannaesnaar prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT amandacmcguire prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT sungeunwou prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT gemmamedinagomez prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT sheenekim prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT cherylbbock prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT dyannmsegvich prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT bhavanasolanky prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT dineshdeelchand prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT antoniovidalpuig prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT nicholasjwareham prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT geraldishulman prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT fredrikkarpe prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT roytaylor prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT bartholomewapederson prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT peterjroach prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT stephenorahilly prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice AT annaadepaoliroach prevalentvariantinppp1r3aimpairsglycogensynthesisandreducesmuscleglycogencontentinhumansandmice |