Full text data of GYS1
GYS1
(GYS)
[Confidence: low (only semi-automatic identification from reviews)]
Glycogen [starch] synthase, muscle; 2.4.1.11
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Glycogen [starch] synthase, muscle; 2.4.1.11
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P13807
ID GYS1_HUMAN Reviewed; 737 AA.
AC P13807; Q9BTT9;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1996, sequence version 2.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Glycogen [starch] synthase, muscle;
DE EC=2.4.1.11;
GN Name=GYS1; Synonyms=GYS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Muscle;
RX PubMed=2493642; DOI=10.1073/pnas.86.5.1443;
RA Browner M.F., Nakano K., Bang A.G., Fletterick R.J.;
RT "Human muscle glycogen synthase cDNA sequence: a negatively charged
RT protein with an asymmetric charge distribution.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:1443-1447(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT NIDDM SER-464.
RX PubMed=7657035; DOI=10.2337/diab.44.9.1099;
RA Orho M., Nikula-Ijas P., Schalin-Jantti C., Permutt M.A., Groop L.C.;
RT "Isolation and characterization of the human muscle glycogen synthase
RT gene.";
RL Diabetes 44:1099-1105(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Endometrium;
RX PubMed=9010351; DOI=10.1016/S0960-0760(96)00138-0;
RA Su X., Schuler L., Shapiro S.S.;
RT "Cloning and characterization of a glycogen synthase cDNA from human
RT endometrium.";
RL J. Steroid Biochem. Mol. Biol. 59:459-465(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Kidney, Lymph, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PHOSPHORYLATION AT SER-641, AND MUTAGENESIS OF SER-641 AND SER-645.
RX PubMed=16275910; DOI=10.1073/pnas.0508481102;
RA Wilson W.A., Skurat A.V., Probst B., de Paoli-Roach A., Roach P.J.,
RA Rutter J.;
RT "Control of mammalian glycogen synthase by PAS kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:16596-16601(2005).
RN [8]
RP INTERACTION WITH GYG1.
RX PubMed=17055998; DOI=10.1016/j.abb.2006.09.024;
RA Skurat A.V., Dietrich A.D., Roach P.J.;
RT "Interaction between glycogenin and glycogen synthase.";
RL Arch. Biochem. Biophys. 456:93-97(2006).
RN [9]
RP INVOLVEMENT IN GSD0B.
RX PubMed=17928598; DOI=10.1056/NEJMoa066691;
RA Kollberg G., Tulinius M., Gilljam T., Oestman-Smith I., Forsander G.,
RA Jotorp P., Oldfors A., Holme E.;
RT "Cardiomyopathy and exercise intolerance in muscle glycogen storage
RT disease 0.";
RL N. Engl. J. Med. 357:1507-1514(2007).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-641; SER-645 AND
RP SER-649, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-727, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP DEPHOSPHORYLATION AT SER-641 AND SER-645 BY PP1.
RX PubMed=21668450; DOI=10.1111/j.1471-4159.2011.07345.x;
RA Kelsall I.R., Voss M., Munro S., Cuthbertson D.J., Cohen P.T.;
RT "R3F, a novel membrane-associated glycogen targeting subunit of
RT protein phosphatase 1 regulates glycogen synthase in astrocytoma cells
RT in response to glucose and extracellular signals.";
RL J. Neurochem. 118:596-610(2011).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
CC -!- FUNCTION: Transfers the glycosyl residue from UDP-Glc to the non-
CC reducing end of alpha-1,4-glucan.
CC -!- CATALYTIC ACTIVITY: UDP-glucose ((1->4)-alpha-D-glucosyl)(n) = UDP
CC + ((1->4)-alpha-D-glucosyl)(n+1).
CC -!- ENZYME REGULATION: Allosteric activation by glucose-6-phosphate.
CC Phosphorylation reduces the activity towards UDP-glucose. When in
CC the non-phosphorylated state, glycogen synthase does not require
CC glucose-6-phosphate as an allosteric activator; when
CC phosphorylated it does (By similarity).
CC -!- PATHWAY: Glycan biosynthesis; glycogen biosynthesis.
CC -!- SUBUNIT: Interacts with GYG1.
CC -!- INTERACTION:
CC P46976:GYG1; NbExp=4; IntAct=EBI-740553, EBI-740533;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P13807-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P13807-2; Sequence=VSP_042745;
CC Note=No experimental confirmation available;
CC -!- PTM: Phosphorylation at Ser-8 by AMPK inactivates the enzyme
CC activity. Primed phosphorylation at Ser-657 (site 5) by CSNK2A1
CC and CSNK2A2 is required for inhibitory phosphorylation at Ser-641
CC (site 3a), Ser-645 (site 3b), Ser-649 (site 3c) and Ser-653 (site
CC 4) by GSK3A an GSK3B (By similarity). Phosphorylated at Ser-641 by
CC DYRK2, leading to inactivation (By similarity). Phosphorylated at
CC Ser-641 by PASK, leading to inactivation; phosphorylation by PASK
CC is inhibited by glycogen. Dephosphorylation at Ser-641 and Ser-645
CC by PP1 activates the enzyme.
CC -!- DISEASE: Muscle glycogen storage disease 0 (GSD0b) [MIM:611556]:
CC Metabolic disorder characterized by fasting hypoglycemia
CC presenting in infancy or early childhood. The role of muscle
CC glycogen is to provide critical energy during bursts of activity
CC and sustained muscle work. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the glycosyltransferase 3 family.
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DR EMBL; J04501; AAA88046.1; -; mRNA.
DR EMBL; Z33622; CAA83916.1; -; Genomic_DNA.
DR EMBL; Z33623; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33609; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33624; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33625; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33626; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33610; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33627; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33628; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33629; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33630; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33631; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33633; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; U32573; AAB60385.1; -; mRNA.
DR EMBL; AC008687; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC026803; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC098792; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471177; EAW52424.1; -; Genomic_DNA.
DR EMBL; BC002617; AAH02617.1; -; mRNA.
DR EMBL; BC003182; AAH03182.1; -; mRNA.
DR EMBL; BC007688; AAH07688.1; -; mRNA.
DR PIR; A32156; A32156.
DR RefSeq; NP_001155059.1; NM_001161587.1.
DR RefSeq; NP_002094.2; NM_002103.4.
DR UniGene; Hs.386225; -.
DR ProteinModelPortal; P13807; -.
DR SMR; P13807; 23-621.
DR IntAct; P13807; 17.
DR MINT; MINT-1451793; -.
DR STRING; 9606.ENSP00000317904; -.
DR BindingDB; P13807; -.
DR CAZy; GT3; Glycosyltransferase Family 3.
DR PhosphoSite; P13807; -.
DR DMDM; 1351366; -.
DR PaxDb; P13807; -.
DR PRIDE; P13807; -.
DR DNASU; 2997; -.
DR Ensembl; ENST00000263276; ENSP00000263276; ENSG00000104812.
DR Ensembl; ENST00000323798; ENSP00000317904; ENSG00000104812.
DR GeneID; 2997; -.
DR KEGG; hsa:2997; -.
DR UCSC; uc002plp.3; human.
DR CTD; 2997; -.
DR GeneCards; GC19M049471; -.
DR HGNC; HGNC:4706; GYS1.
DR HPA; CAB007793; -.
DR MIM; 138570; gene.
DR MIM; 611556; phenotype.
DR neXtProt; NX_P13807; -.
DR Orphanet; 137625; Glycogen storage disease due to muscle and heart glycogen synthase deficiency.
DR PharmGKB; PA29084; -.
DR eggNOG; COG0438; -.
DR HOGENOM; HOG000160890; -.
DR HOVERGEN; HBG001960; -.
DR InParanoid; P13807; -.
DR KO; K00693; -.
DR OMA; FAMKRHG; -.
DR OrthoDB; EOG741Z1N; -.
DR PhylomeDB; P13807; -.
DR BioCyc; MetaCyc:HS02622-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00164; -.
DR ChiTaRS; GYS1; human.
DR GenomeRNAi; 2997; -.
DR NextBio; 11884; -.
DR PRO; PR:P13807; -.
DR ArrayExpress; P13807; -.
DR Bgee; P13807; -.
DR CleanEx; HS_GYS1; -.
DR Genevestigator; P13807; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016234; C:inclusion body; IEA:Ensembl.
DR GO; GO:0005536; F:glucose binding; IEA:Ensembl.
DR GO; GO:0004373; F:glycogen (starch) synthase activity; IDA:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; TAS:Reactome.
DR GO; GO:0005978; P:glycogen biosynthetic process; IDA:UniProtKB.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR InterPro; IPR008631; Glycogen_synth.
DR PANTHER; PTHR10176; PTHR10176; 1.
DR Pfam; PF05693; Glycogen_syn; 1.
PE 1: Evidence at protein level;
KW Allosteric enzyme; Alternative splicing; Complete proteome;
KW Diabetes mellitus; Disease mutation; Glycogen biosynthesis;
KW Glycosyltransferase; Phosphoprotein; Polymorphism; Reference proteome;
KW Transferase.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 737 Glycogen [starch] synthase, muscle.
FT /FTId=PRO_0000194763.
FT BINDING 39 39 UDP-glucose (By similarity).
FT MOD_RES 8 8 Phosphoserine; by AMPK and PKA (By
FT similarity).
FT MOD_RES 11 11 Phosphoserine (By similarity).
FT MOD_RES 641 641 Phosphoserine.
FT MOD_RES 645 645 Phosphoserine.
FT MOD_RES 649 649 Phosphoserine.
FT MOD_RES 653 653 Phosphoserine; by GSK3-alpha and GSK3-
FT beta (By similarity).
FT MOD_RES 657 657 Phosphoserine; by CK2 (By similarity).
FT MOD_RES 698 698 Phosphoserine (By similarity).
FT MOD_RES 727 727 Phosphoserine.
FT VAR_SEQ 101 164 Missing (in isoform 2).
FT /FTId=VSP_042745.
FT VARIANT 108 108 I -> M (in dbSNP:rs5455).
FT /FTId=VAR_037958.
FT VARIANT 130 130 K -> E (in dbSNP:rs5456).
FT /FTId=VAR_014727.
FT VARIANT 283 283 N -> S (in dbSNP:rs5461).
FT /FTId=VAR_014728.
FT VARIANT 359 359 E -> G (in dbSNP:rs5465).
FT /FTId=VAR_014729.
FT VARIANT 416 416 M -> V (in dbSNP:rs5447).
FT /FTId=VAR_014730.
FT VARIANT 464 464 G -> S (in NIDDM).
FT /FTId=VAR_007859.
FT VARIANT 619 619 E -> Q (in dbSNP:rs5450).
FT /FTId=VAR_014731.
FT VARIANT 691 691 P -> A (in dbSNP:rs5453).
FT /FTId=VAR_014732.
FT MUTAGEN 641 641 S->A: Abolishes PASK-mediated
FT phosphorylation.
FT MUTAGEN 645 645 S->A: Does not affect PASK-mediated
FT phosphorylation.
FT CONFLICT 136 136 T -> I (in Ref. 1; AAA88046 and 3;
FT AAB60385).
FT CONFLICT 462 462 Missing (in Ref. 3; AAB60385).
FT CONFLICT 608 608 A -> D (in Ref. 3; AAB60385).
FT CONFLICT 706 706 S -> R (in Ref. 1; AAA88046 and 3;
FT AAB60385).
SQ SEQUENCE 737 AA; 83786 MW; 0E321BBFDEB0BD7F CRC64;
MPLNRTLSMS SLPGLEDWED EFDLENAVLF EVAWEVANKV GGIYTVLQTK AKVTGDEWGD
NYFLVGPYTE QGVRTQVELL EAPTPALKRT LDSMNSKGCK VYFGRWLIEG GPLVVLLDVG
ASAWALERWK GELWDTCNIG VPWYDREAND AVLFGFLTTW FLGEFLAQSE EKPHVVAHFH
EWLAGVGLCL CRARRLPVAT IFTTHATLLG RYLCAGAVDF YNNLENFNVD KEAGERQIYH
RYCMERAAAH CAHVFTTVSQ ITAIEAQHLL KRKPDIVTPN GLNVKKFSAM HEFQNLHAQS
KARIQEFVRG HFYGHLDFNL DKTLYFFIAG RYEFSNKGAD VFLEALARLN YLLRVNGSEQ
TVVAFFIMPA RTNNFNVETL KGQAVRKQLW DTANTVKEKF GRKLYESLLV GSLPDMNKML
DKEDFTMMKR AIFATQRQSF PPVCTHNMLD DSSDPILTTI RRIGLFNSSA DRVKVIFHPE
FLSSTSPLLP VDYEEFVRGC HLGVFPSYYE PWGYTPAECT VMGIPSISTN LSGFGCFMEE
HIADPSAYGI YILDRRFRSL DDSCSQLTSF LYSFCQQSRR QRIIQRNRTE RLSDLLDWKY
LGRYYMSARH MALSKAFPEH FTYEPNEADA AQGYRYPRPA SVPPSPSLSR HSSPHQSEDE
EDPRNGPLEE DGERYDEDEE AAKDRRNIRA PEWPRRASCT SSTSGSKRNS VDTATSSSLS
TPSEPLSPTS SLGEERN
//
ID GYS1_HUMAN Reviewed; 737 AA.
AC P13807; Q9BTT9;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1996, sequence version 2.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Glycogen [starch] synthase, muscle;
DE EC=2.4.1.11;
GN Name=GYS1; Synonyms=GYS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Muscle;
RX PubMed=2493642; DOI=10.1073/pnas.86.5.1443;
RA Browner M.F., Nakano K., Bang A.G., Fletterick R.J.;
RT "Human muscle glycogen synthase cDNA sequence: a negatively charged
RT protein with an asymmetric charge distribution.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:1443-1447(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT NIDDM SER-464.
RX PubMed=7657035; DOI=10.2337/diab.44.9.1099;
RA Orho M., Nikula-Ijas P., Schalin-Jantti C., Permutt M.A., Groop L.C.;
RT "Isolation and characterization of the human muscle glycogen synthase
RT gene.";
RL Diabetes 44:1099-1105(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Endometrium;
RX PubMed=9010351; DOI=10.1016/S0960-0760(96)00138-0;
RA Su X., Schuler L., Shapiro S.S.;
RT "Cloning and characterization of a glycogen synthase cDNA from human
RT endometrium.";
RL J. Steroid Biochem. Mol. Biol. 59:459-465(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Kidney, Lymph, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PHOSPHORYLATION AT SER-641, AND MUTAGENESIS OF SER-641 AND SER-645.
RX PubMed=16275910; DOI=10.1073/pnas.0508481102;
RA Wilson W.A., Skurat A.V., Probst B., de Paoli-Roach A., Roach P.J.,
RA Rutter J.;
RT "Control of mammalian glycogen synthase by PAS kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:16596-16601(2005).
RN [8]
RP INTERACTION WITH GYG1.
RX PubMed=17055998; DOI=10.1016/j.abb.2006.09.024;
RA Skurat A.V., Dietrich A.D., Roach P.J.;
RT "Interaction between glycogenin and glycogen synthase.";
RL Arch. Biochem. Biophys. 456:93-97(2006).
RN [9]
RP INVOLVEMENT IN GSD0B.
RX PubMed=17928598; DOI=10.1056/NEJMoa066691;
RA Kollberg G., Tulinius M., Gilljam T., Oestman-Smith I., Forsander G.,
RA Jotorp P., Oldfors A., Holme E.;
RT "Cardiomyopathy and exercise intolerance in muscle glycogen storage
RT disease 0.";
RL N. Engl. J. Med. 357:1507-1514(2007).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-641; SER-645 AND
RP SER-649, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-727, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP DEPHOSPHORYLATION AT SER-641 AND SER-645 BY PP1.
RX PubMed=21668450; DOI=10.1111/j.1471-4159.2011.07345.x;
RA Kelsall I.R., Voss M., Munro S., Cuthbertson D.J., Cohen P.T.;
RT "R3F, a novel membrane-associated glycogen targeting subunit of
RT protein phosphatase 1 regulates glycogen synthase in astrocytoma cells
RT in response to glucose and extracellular signals.";
RL J. Neurochem. 118:596-610(2011).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
CC -!- FUNCTION: Transfers the glycosyl residue from UDP-Glc to the non-
CC reducing end of alpha-1,4-glucan.
CC -!- CATALYTIC ACTIVITY: UDP-glucose ((1->4)-alpha-D-glucosyl)(n) = UDP
CC + ((1->4)-alpha-D-glucosyl)(n+1).
CC -!- ENZYME REGULATION: Allosteric activation by glucose-6-phosphate.
CC Phosphorylation reduces the activity towards UDP-glucose. When in
CC the non-phosphorylated state, glycogen synthase does not require
CC glucose-6-phosphate as an allosteric activator; when
CC phosphorylated it does (By similarity).
CC -!- PATHWAY: Glycan biosynthesis; glycogen biosynthesis.
CC -!- SUBUNIT: Interacts with GYG1.
CC -!- INTERACTION:
CC P46976:GYG1; NbExp=4; IntAct=EBI-740553, EBI-740533;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P13807-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P13807-2; Sequence=VSP_042745;
CC Note=No experimental confirmation available;
CC -!- PTM: Phosphorylation at Ser-8 by AMPK inactivates the enzyme
CC activity. Primed phosphorylation at Ser-657 (site 5) by CSNK2A1
CC and CSNK2A2 is required for inhibitory phosphorylation at Ser-641
CC (site 3a), Ser-645 (site 3b), Ser-649 (site 3c) and Ser-653 (site
CC 4) by GSK3A an GSK3B (By similarity). Phosphorylated at Ser-641 by
CC DYRK2, leading to inactivation (By similarity). Phosphorylated at
CC Ser-641 by PASK, leading to inactivation; phosphorylation by PASK
CC is inhibited by glycogen. Dephosphorylation at Ser-641 and Ser-645
CC by PP1 activates the enzyme.
CC -!- DISEASE: Muscle glycogen storage disease 0 (GSD0b) [MIM:611556]:
CC Metabolic disorder characterized by fasting hypoglycemia
CC presenting in infancy or early childhood. The role of muscle
CC glycogen is to provide critical energy during bursts of activity
CC and sustained muscle work. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the glycosyltransferase 3 family.
CC -----------------------------------------------------------------------
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DR EMBL; J04501; AAA88046.1; -; mRNA.
DR EMBL; Z33622; CAA83916.1; -; Genomic_DNA.
DR EMBL; Z33623; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33609; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33624; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33625; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33626; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33610; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33627; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33628; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33629; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33630; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33631; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; Z33633; CAA83916.1; JOINED; Genomic_DNA.
DR EMBL; U32573; AAB60385.1; -; mRNA.
DR EMBL; AC008687; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC026803; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC098792; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471177; EAW52424.1; -; Genomic_DNA.
DR EMBL; BC002617; AAH02617.1; -; mRNA.
DR EMBL; BC003182; AAH03182.1; -; mRNA.
DR EMBL; BC007688; AAH07688.1; -; mRNA.
DR PIR; A32156; A32156.
DR RefSeq; NP_001155059.1; NM_001161587.1.
DR RefSeq; NP_002094.2; NM_002103.4.
DR UniGene; Hs.386225; -.
DR ProteinModelPortal; P13807; -.
DR SMR; P13807; 23-621.
DR IntAct; P13807; 17.
DR MINT; MINT-1451793; -.
DR STRING; 9606.ENSP00000317904; -.
DR BindingDB; P13807; -.
DR CAZy; GT3; Glycosyltransferase Family 3.
DR PhosphoSite; P13807; -.
DR DMDM; 1351366; -.
DR PaxDb; P13807; -.
DR PRIDE; P13807; -.
DR DNASU; 2997; -.
DR Ensembl; ENST00000263276; ENSP00000263276; ENSG00000104812.
DR Ensembl; ENST00000323798; ENSP00000317904; ENSG00000104812.
DR GeneID; 2997; -.
DR KEGG; hsa:2997; -.
DR UCSC; uc002plp.3; human.
DR CTD; 2997; -.
DR GeneCards; GC19M049471; -.
DR HGNC; HGNC:4706; GYS1.
DR HPA; CAB007793; -.
DR MIM; 138570; gene.
DR MIM; 611556; phenotype.
DR neXtProt; NX_P13807; -.
DR Orphanet; 137625; Glycogen storage disease due to muscle and heart glycogen synthase deficiency.
DR PharmGKB; PA29084; -.
DR eggNOG; COG0438; -.
DR HOGENOM; HOG000160890; -.
DR HOVERGEN; HBG001960; -.
DR InParanoid; P13807; -.
DR KO; K00693; -.
DR OMA; FAMKRHG; -.
DR OrthoDB; EOG741Z1N; -.
DR PhylomeDB; P13807; -.
DR BioCyc; MetaCyc:HS02622-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00164; -.
DR ChiTaRS; GYS1; human.
DR GenomeRNAi; 2997; -.
DR NextBio; 11884; -.
DR PRO; PR:P13807; -.
DR ArrayExpress; P13807; -.
DR Bgee; P13807; -.
DR CleanEx; HS_GYS1; -.
DR Genevestigator; P13807; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016234; C:inclusion body; IEA:Ensembl.
DR GO; GO:0005536; F:glucose binding; IEA:Ensembl.
DR GO; GO:0004373; F:glycogen (starch) synthase activity; IDA:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; TAS:Reactome.
DR GO; GO:0005978; P:glycogen biosynthetic process; IDA:UniProtKB.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR InterPro; IPR008631; Glycogen_synth.
DR PANTHER; PTHR10176; PTHR10176; 1.
DR Pfam; PF05693; Glycogen_syn; 1.
PE 1: Evidence at protein level;
KW Allosteric enzyme; Alternative splicing; Complete proteome;
KW Diabetes mellitus; Disease mutation; Glycogen biosynthesis;
KW Glycosyltransferase; Phosphoprotein; Polymorphism; Reference proteome;
KW Transferase.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 737 Glycogen [starch] synthase, muscle.
FT /FTId=PRO_0000194763.
FT BINDING 39 39 UDP-glucose (By similarity).
FT MOD_RES 8 8 Phosphoserine; by AMPK and PKA (By
FT similarity).
FT MOD_RES 11 11 Phosphoserine (By similarity).
FT MOD_RES 641 641 Phosphoserine.
FT MOD_RES 645 645 Phosphoserine.
FT MOD_RES 649 649 Phosphoserine.
FT MOD_RES 653 653 Phosphoserine; by GSK3-alpha and GSK3-
FT beta (By similarity).
FT MOD_RES 657 657 Phosphoserine; by CK2 (By similarity).
FT MOD_RES 698 698 Phosphoserine (By similarity).
FT MOD_RES 727 727 Phosphoserine.
FT VAR_SEQ 101 164 Missing (in isoform 2).
FT /FTId=VSP_042745.
FT VARIANT 108 108 I -> M (in dbSNP:rs5455).
FT /FTId=VAR_037958.
FT VARIANT 130 130 K -> E (in dbSNP:rs5456).
FT /FTId=VAR_014727.
FT VARIANT 283 283 N -> S (in dbSNP:rs5461).
FT /FTId=VAR_014728.
FT VARIANT 359 359 E -> G (in dbSNP:rs5465).
FT /FTId=VAR_014729.
FT VARIANT 416 416 M -> V (in dbSNP:rs5447).
FT /FTId=VAR_014730.
FT VARIANT 464 464 G -> S (in NIDDM).
FT /FTId=VAR_007859.
FT VARIANT 619 619 E -> Q (in dbSNP:rs5450).
FT /FTId=VAR_014731.
FT VARIANT 691 691 P -> A (in dbSNP:rs5453).
FT /FTId=VAR_014732.
FT MUTAGEN 641 641 S->A: Abolishes PASK-mediated
FT phosphorylation.
FT MUTAGEN 645 645 S->A: Does not affect PASK-mediated
FT phosphorylation.
FT CONFLICT 136 136 T -> I (in Ref. 1; AAA88046 and 3;
FT AAB60385).
FT CONFLICT 462 462 Missing (in Ref. 3; AAB60385).
FT CONFLICT 608 608 A -> D (in Ref. 3; AAB60385).
FT CONFLICT 706 706 S -> R (in Ref. 1; AAA88046 and 3;
FT AAB60385).
SQ SEQUENCE 737 AA; 83786 MW; 0E321BBFDEB0BD7F CRC64;
MPLNRTLSMS SLPGLEDWED EFDLENAVLF EVAWEVANKV GGIYTVLQTK AKVTGDEWGD
NYFLVGPYTE QGVRTQVELL EAPTPALKRT LDSMNSKGCK VYFGRWLIEG GPLVVLLDVG
ASAWALERWK GELWDTCNIG VPWYDREAND AVLFGFLTTW FLGEFLAQSE EKPHVVAHFH
EWLAGVGLCL CRARRLPVAT IFTTHATLLG RYLCAGAVDF YNNLENFNVD KEAGERQIYH
RYCMERAAAH CAHVFTTVSQ ITAIEAQHLL KRKPDIVTPN GLNVKKFSAM HEFQNLHAQS
KARIQEFVRG HFYGHLDFNL DKTLYFFIAG RYEFSNKGAD VFLEALARLN YLLRVNGSEQ
TVVAFFIMPA RTNNFNVETL KGQAVRKQLW DTANTVKEKF GRKLYESLLV GSLPDMNKML
DKEDFTMMKR AIFATQRQSF PPVCTHNMLD DSSDPILTTI RRIGLFNSSA DRVKVIFHPE
FLSSTSPLLP VDYEEFVRGC HLGVFPSYYE PWGYTPAECT VMGIPSISTN LSGFGCFMEE
HIADPSAYGI YILDRRFRSL DDSCSQLTSF LYSFCQQSRR QRIIQRNRTE RLSDLLDWKY
LGRYYMSARH MALSKAFPEH FTYEPNEADA AQGYRYPRPA SVPPSPSLSR HSSPHQSEDE
EDPRNGPLEE DGERYDEDEE AAKDRRNIRA PEWPRRASCT SSTSGSKRNS VDTATSSSLS
TPSEPLSPTS SLGEERN
//
MIM
138570
*RECORD*
*FIELD* NO
138570
*FIELD* TI
*138570 GLYCOGEN SYNTHASE 1; GYS1
;;GLYCOGEN SYNTHASE, MUSCLE;;
GYS
*FIELD* TX
DESCRIPTION
read more
Glycogen is a high molecular mass polysaccharide that serves as a
repository of glucose for use in times of metabolic need. Glycogen
synthase (EC 2.4.1.11) catalyzes the addition of glucose monomers to the
growing glycogen molecule through the formation of alpha-1,4-glycoside
linkages (Pederson et al., 2004).
CLONING
Browner et al. (1989) cloned and sequenced a cDNA for human muscle
glycogen synthase. They found that it encodes a protein of 737 amino
acids. Its primary structure is not related either to bacterial glycogen
synthase or to any glycogen phosphorylase. They concluded that the
glycogen synthase mRNA expressed in both fetal and adult heart and
skeletal muscle tissue are the same, based on the size of mRNA species
that were hybridized. Liver glycogen synthase is distinct (see GYS2,
138571).
MAPPING
By Southern blot analysis of somatic cell hybrid DNAs, Groop et al.
(1993) determined that the GYS1 gene is located on chromosome 19. Lehto
et al. (1993) regionalized the GYS gene to 19q13.3 by fluorescence in
situ hybridization.
GENE FUNCTION
To examine whether defective muscle GYS1 expression is associated with
impaired glycogen synthesis in type 2 diabetes (see 125853) and whether
the defect is inherited or acquired, Huang et al. (2000) measured GYS1
gene expression and enzyme activity in muscle biopsies taken before and
after an insulin clamp in 12 monozygotic twin pairs discordant for type
2 diabetes and in 12 matched control subjects. The effect of insulin on
GYS1 fractional activity, when expressed as the increment over the basal
values, was significantly impaired in diabetic, but not in nondiabetic,
twins compared with that in control subjects. Insulin increased GYS1
mRNA expression in control subjects and in nondiabetic and diabetic
twins. The effect of insulin on GYS1 expression was, however,
significantly reduced in the diabetic (P less than 0.003), but not in
the nondiabetic, twins, compared with that in control subjects. The
postclamp GYS1 mRNA levels correlated strongly with the hemoglobin A1c
levels (r = -0.61; P less than 0.001). The authors concluded that
insulin stimulates GYS1 mRNA expression and that impaired stimulation of
GYS1 gene expression by insulin in patients with type 2 diabetes is
acquired and most likely is secondary to chronic hyperglycemia.
Kollberg et al. (2007) summarized the functions of muscle glycogen
synthase and liver glycogen synthase, the key enzymes of glycogen
synthesis, encoded by the GYS1 and GYS2 (138571) genes, respectively.
The liver enzyme expression is restricted to the liver, whereas the
muscle enzyme is ubiquitously expressed. Liver glycogen serves as a pool
to maintain the blood glucose level during fasting, whereas muscle
glycogen synthesis accounts for disposal of up to 90% of ingested
glucose. The role of muscle and heart glycogen is to provide critical
energy during bursts of activity and sustained muscle work. Deficiency
of either muscle or liver glycogen synthase leads to distinct
phenotypes; see 240600 for a description of liver glycogen synthase
deficiency.
MOLECULAR GENETICS
- Muscle Glycogen Storage Disease
Kollberg et al. (2007) described 3 sibs with profound muscle and heart
glycogen deficiency (GSD 0b; 611556) caused by homozygosity for a stop
codon mutation in the GYS1 gene (R462X; 138570.0001). Several findings
in the patients were in accordance with the findings in muscle glycogen
synthase knockout mice (Pederson et al., 2004, 2005, 2005).
- Polymorphic Alleles
Using a human complementary probe for glycogen synthase, the restriction
enzyme XbaI, and Southern blot analysis, Groop et al. (1993) identified
2 polymorphic alleles, A1 and A2, in the GYS1 gene. The study was
performed in Helsinki in Finnish patients. The A1A2 or A2A2 genotype was
found in 30% of 107 patients with noninsulin-dependent diabetes mellitus
(NIDDM; 125853) but in only 8% of 164 nondiabetic subjects without a
family history of NIDDM (P less than 0.001). Diabetic patients with the
A2 allele had a stronger family history of NIDDM (P = 0.019), a higher
prevalence of hypertension (P = 0.008), and a more severe defect in
insulin-stimulated glucose storage (P = 0.001) than the diabetic
patients with the A1 allele. The concentration of the glycogen synthase
protein in biopsy specimens of skeletal muscle from the patients with
the A2 allele was normal, however, suggesting that expression of the
gene was unaltered. The XbaI polymorphism was due to a change of a
single base in an intron: the A2 allele had a substitution of thymidine
for cytosine (CCTAGA to TCTAGA) 302 bp upstream from position 1970 of
the cDNA. The storage of glucose as glycogen in skeletal muscle is
frequently impaired in patients with NIDDM and their nondiabetic
relatives. The association of the GYS1 polymorphism with diabetes could
not be confirmed in France (Zouali et al., 1993) or Japan (Kadowaki et
al., 1993).
In a genotype-discordant analysis of 122 sex-matched Finnish sib pairs
from families with type 2 diabetes, Orho-Melander et al. (1999) found
that sibs with the A2 variant of the XbaI polymorphism in the GYS1 gene
had more hypertension, obesity, and microalbuminuria and were treated
more often with insulin and antihypertensive medication than their sibs
with the A1 variant. Diabetic A2 carriers had higher triglyceride and
lower HDL cholesterol concentrations and an earlier age of onset of
diabetes than diabetic sibs with the A1 variant. In nondiabetic sib
pairs, the presence of the A2 variant was associated with higher
diastolic blood pressure. Orho-Melander et al. (1999) replicated the
association between the XbaI polymorphism and type 2 diabetes in 216
patients and 115 unrelated controls (p = 0.013).
ANIMAL MODEL
Inbred mouse strains fed on a diabetogenic diet (high in fat and
sucrose) differ in their propensities to develop features analogous to
type 2 diabetes mellitus. To define chromosomal locations that control
these characteristics, Seldin et al. (1994) studied recombinant inbred
strains from diabetes-prone C57BL/6J and diabetes-resistant A/J strains.
Hyperglycemia correlated with the marker D7Mit25 on mouse chromosome 7.
This putative susceptibility locus is consistent with that of the
glycogen synthase gene, which was implicated by Groop et al. (1993) in
the pathogenesis of type 2 diabetes in the human. Seldin et al. (1994)
found that fractional glycogen synthase activity in isolated muscle was
significantly lower in normal B/6J diabetes-prone mice than in normal
diabetes-resistant A/J mice, a finding similar to that reported in
relatives of human patients with type 2 diabetes.
Pederson et al. (2004) found that 90% of Gys1 -/- mouse pups died
without taking a breath due to failure of the lungs to inflate.
Examination of Gys1 -/- embryos at 14.5 days postcoitum revealed venous
and pulmonary congestion, severely hemorrhagic livers, and abnormal
heart morphology, including thin ventricular walls resulting from
decreased cell proliferation. Gys1 -/- mice that survived to adulthood
had normal systolic blood pressure, heart rate, and electrocardiogram
and no gross heart abnormalities, although there was a trend toward
larger left ventricular mass, and the hearts of older males showed
significant fibrosis. Biochemical analysis of skeletal muscle and heart
of Gys1 -/- mice revealed the lack of glycogen; heterozygotes had
glycogen levels that tended to be lower than those of wildtype mice.
Polysaccharide storage myopathy (PSSM) is a glycogenosis in horses
characterized by abnormal glycogen accumulation in skeletal muscle and
muscle damage with exertion. In PSSM-affected horses, McCue et al.
(2008) identified a G-to-A change in exon 6 of the Gys1 gene, resulting
in an arg309-to-his (R309H) substitution. R309 is conserved in human
GYS1 and lies in a region that shares extensive identity with human
GYS1. Functional analysis demonstrated elevated glycogen synthase
activity in PSSM horses, indicating that R309H is a gain-of-function
mutation.
*FIELD* AV
.0001
GLYCOGEN STORAGE DISEASE 0, MUSCLE
GYS1, ARG462TER
In 3 sibs with muscle glycogen storage disease 0 (611556), the offspring
of consanguineous parents of Syrian origin, Kollberg et al. (2007)
detected a 1384C-T transition in exon 11 of the GYS1 gene, which changed
CGA, coding for arginine, to a TGA terminal signal. This premature stop
codon was predicted to result in truncation of muscle glycogen synthase
at amino acid residue 462 (R462X). Thus, the part of the enzyme
harboring the active site was predicted to be lost.
*FIELD* RF
1. Browner, M. F.; Nakano, K.; Bang, A. G.; Fletterick, R. J.: Human
muscle glycogen synthase cDNA sequence: a negatively charged protein
with an asymmetric charge distribution. Proc. Nat. Acad. Sci. 86:
1443-1447, 1989.
2. Groop, L. C.; Kankuri, M.; Schalin-Jantti, C.; Ekstrand, A.; Nikula-Ijas,
P.; Widen, E.; Kuismanen, E.; Eriksson, J.; Franssila-Kallunki, A.;
Saloranta, C.; Koskimies, S.: Association between polymorphism of
the glycogen synthase gene and non-insulin-dependent diabetes mellitus. New
Eng. J. Med. 328: 10-14, 1993. Note: Erratum: New Eng. J. Med. 328:
1136 only, 1993.
3. Huang, X.; Vaag, A.; Hansson, M.; Weng, J.; Laurila, E.; Groop,
L.: Impaired insulin-stimulated expression of the glycogen synthase
gene in skeletal muscle of type 2 diabetic patients is acquired rather
than inherited. J. Clin. Endocr. Metab. 85: 1584-1590, 2000.
4. Kadowaki, T.; Kadowaki, H.; Yazaki, Y.: Polymorphism of the glycogen
synthase gene and non-insulin-dependent diabetes mellitus. (Letter) New
Eng. J. Med. 328: 1569, 1993.
5. Kollberg, G.; Tulinius, M.; Gilljam, T.; Ostman-Smith, I.; Forsander,
G.; Jotorp, P.; Oldfors, A.; Holme, E.: Cardiomyopathy and exercise
intolerance in muscle glycogen storage disease 0. New Eng. J. Med. 357:
1507-1514, 2007.
6. Lehto, M.; Stoffel, M.; Groop, L.; Espinosa, R., III; Le Beau,
M. M.; Bell, G. I.: Assignment of the gene encoding glycogen synthase
(GYS) to human chromosome 19, band q13.3. Genomics 15: 460-461,
1993.
7. McCue, M. E.; Valberg, S. J.; Miller, M. B.; Wade, C.; DiMauro,
S.; Akman, H. O.; Mickelson, J. R.: Glycogen synthase (GYS1) mutation
causes a novel skeletal muscle glycogenosis. Genomics 91: 458-466,
2008.
8. Orho-Melander, M.; Almgren, P.; Kanninen, T.; Forsblom, C.; Groop,
L. C.: A paired-sibling analysis of the XbaI polymorphism in the
muscle glycogen synthase gene. Diabetologia 42: 1138-1145, 1999.
9. Pederson, B. A.; Chen, H.; Schroeder, J. M.; Shou, W.; DePaoli-Roach,
A. A.; Roach, P. J.: Abnormal cardiac development in the absence
of heart glycogen. Molec. Cell. Biol. 24: 7179-7187, 2004.
10. Pederson, B. A.; Chen, H.; Schroeder, J. M.; Shou, W.; DePaoli-Roach,
A. A.; Roach, P. J.: Abnormal cardiac development in the absence
of heart glycogen. Molec. Cell. Biol. 24: 7179-7187, 2004.
11. Pederson, B. A.; Cope, C. R.; Schroeder, J. M.; Smith, M. W.;
Irimia, J. M.; Thurberg, B. L.; DePaoli-Roach, A. A.; Roach, P. J.
: Exercise capacity of mice genetically lacking muscle glycogen synthase:
in mice, muscle glycogen is not essential for exercise. J. Biol.
Chem. 280: 17260-17265, 2005.
12. Pederson, B. A.; Schroeder, J. M.; Parker, G. E.; Smith, M. W.;
DePaoli-Roach, A. A.; Roach, P. J.: Glucose metabolism in mice lacking
muscle glycogen synthase. Diabetes 54: 3466-3473, 2005.
13. Seldin, M. F.; Mott, D.; Bhat, D.; Petro, A.; Kuhn, C. M.; Kingsmore,
S. F.; Bogardus, C.; Opara, E.; Feinglos, M. N.; Surwit, R. S.: Glycogen
synthase: a putative locus for diet-induced hyperglycemia. J. Clin.
Invest. 94: 269-276, 1994.
14. Zouali, H.; Velho, G.; Froguel, P.: Polymorphism of the glycogen
synthase gene and non-insulin-dependent diabetes mellitus. (Letter) New
Eng. J. Med. 328: 1568, 1993.
*FIELD* CN
Patricia A. Hartz - updated: 6/6/2008
Patricia A. Hartz - updated: 11/30/2007
Marla J. F. O'Neill - updated: 10/29/2007
Victor A. McKusick - updated: 10/16/2007
John A. Phillips, III - updated: 11/16/2000
*FIELD* CD
Victor A. McKusick: 9/11/1989
*FIELD* ED
carol: 04/12/2013
mgross: 6/11/2008
terry: 6/6/2008
carol: 12/4/2007
mgross: 12/4/2007
terry: 11/30/2007
wwang: 10/29/2007
alopez: 10/26/2007
terry: 10/16/2007
alopez: 1/12/2001
terry: 11/16/2000
terry: 11/6/1996
terry: 6/3/1996
terry: 8/26/1994
warfield: 4/20/1994
carol: 2/16/1994
carol: 6/22/1993
carol: 4/8/1993
carol: 3/18/1993
*RECORD*
*FIELD* NO
138570
*FIELD* TI
*138570 GLYCOGEN SYNTHASE 1; GYS1
;;GLYCOGEN SYNTHASE, MUSCLE;;
GYS
*FIELD* TX
DESCRIPTION
read more
Glycogen is a high molecular mass polysaccharide that serves as a
repository of glucose for use in times of metabolic need. Glycogen
synthase (EC 2.4.1.11) catalyzes the addition of glucose monomers to the
growing glycogen molecule through the formation of alpha-1,4-glycoside
linkages (Pederson et al., 2004).
CLONING
Browner et al. (1989) cloned and sequenced a cDNA for human muscle
glycogen synthase. They found that it encodes a protein of 737 amino
acids. Its primary structure is not related either to bacterial glycogen
synthase or to any glycogen phosphorylase. They concluded that the
glycogen synthase mRNA expressed in both fetal and adult heart and
skeletal muscle tissue are the same, based on the size of mRNA species
that were hybridized. Liver glycogen synthase is distinct (see GYS2,
138571).
MAPPING
By Southern blot analysis of somatic cell hybrid DNAs, Groop et al.
(1993) determined that the GYS1 gene is located on chromosome 19. Lehto
et al. (1993) regionalized the GYS gene to 19q13.3 by fluorescence in
situ hybridization.
GENE FUNCTION
To examine whether defective muscle GYS1 expression is associated with
impaired glycogen synthesis in type 2 diabetes (see 125853) and whether
the defect is inherited or acquired, Huang et al. (2000) measured GYS1
gene expression and enzyme activity in muscle biopsies taken before and
after an insulin clamp in 12 monozygotic twin pairs discordant for type
2 diabetes and in 12 matched control subjects. The effect of insulin on
GYS1 fractional activity, when expressed as the increment over the basal
values, was significantly impaired in diabetic, but not in nondiabetic,
twins compared with that in control subjects. Insulin increased GYS1
mRNA expression in control subjects and in nondiabetic and diabetic
twins. The effect of insulin on GYS1 expression was, however,
significantly reduced in the diabetic (P less than 0.003), but not in
the nondiabetic, twins, compared with that in control subjects. The
postclamp GYS1 mRNA levels correlated strongly with the hemoglobin A1c
levels (r = -0.61; P less than 0.001). The authors concluded that
insulin stimulates GYS1 mRNA expression and that impaired stimulation of
GYS1 gene expression by insulin in patients with type 2 diabetes is
acquired and most likely is secondary to chronic hyperglycemia.
Kollberg et al. (2007) summarized the functions of muscle glycogen
synthase and liver glycogen synthase, the key enzymes of glycogen
synthesis, encoded by the GYS1 and GYS2 (138571) genes, respectively.
The liver enzyme expression is restricted to the liver, whereas the
muscle enzyme is ubiquitously expressed. Liver glycogen serves as a pool
to maintain the blood glucose level during fasting, whereas muscle
glycogen synthesis accounts for disposal of up to 90% of ingested
glucose. The role of muscle and heart glycogen is to provide critical
energy during bursts of activity and sustained muscle work. Deficiency
of either muscle or liver glycogen synthase leads to distinct
phenotypes; see 240600 for a description of liver glycogen synthase
deficiency.
MOLECULAR GENETICS
- Muscle Glycogen Storage Disease
Kollberg et al. (2007) described 3 sibs with profound muscle and heart
glycogen deficiency (GSD 0b; 611556) caused by homozygosity for a stop
codon mutation in the GYS1 gene (R462X; 138570.0001). Several findings
in the patients were in accordance with the findings in muscle glycogen
synthase knockout mice (Pederson et al., 2004, 2005, 2005).
- Polymorphic Alleles
Using a human complementary probe for glycogen synthase, the restriction
enzyme XbaI, and Southern blot analysis, Groop et al. (1993) identified
2 polymorphic alleles, A1 and A2, in the GYS1 gene. The study was
performed in Helsinki in Finnish patients. The A1A2 or A2A2 genotype was
found in 30% of 107 patients with noninsulin-dependent diabetes mellitus
(NIDDM; 125853) but in only 8% of 164 nondiabetic subjects without a
family history of NIDDM (P less than 0.001). Diabetic patients with the
A2 allele had a stronger family history of NIDDM (P = 0.019), a higher
prevalence of hypertension (P = 0.008), and a more severe defect in
insulin-stimulated glucose storage (P = 0.001) than the diabetic
patients with the A1 allele. The concentration of the glycogen synthase
protein in biopsy specimens of skeletal muscle from the patients with
the A2 allele was normal, however, suggesting that expression of the
gene was unaltered. The XbaI polymorphism was due to a change of a
single base in an intron: the A2 allele had a substitution of thymidine
for cytosine (CCTAGA to TCTAGA) 302 bp upstream from position 1970 of
the cDNA. The storage of glucose as glycogen in skeletal muscle is
frequently impaired in patients with NIDDM and their nondiabetic
relatives. The association of the GYS1 polymorphism with diabetes could
not be confirmed in France (Zouali et al., 1993) or Japan (Kadowaki et
al., 1993).
In a genotype-discordant analysis of 122 sex-matched Finnish sib pairs
from families with type 2 diabetes, Orho-Melander et al. (1999) found
that sibs with the A2 variant of the XbaI polymorphism in the GYS1 gene
had more hypertension, obesity, and microalbuminuria and were treated
more often with insulin and antihypertensive medication than their sibs
with the A1 variant. Diabetic A2 carriers had higher triglyceride and
lower HDL cholesterol concentrations and an earlier age of onset of
diabetes than diabetic sibs with the A1 variant. In nondiabetic sib
pairs, the presence of the A2 variant was associated with higher
diastolic blood pressure. Orho-Melander et al. (1999) replicated the
association between the XbaI polymorphism and type 2 diabetes in 216
patients and 115 unrelated controls (p = 0.013).
ANIMAL MODEL
Inbred mouse strains fed on a diabetogenic diet (high in fat and
sucrose) differ in their propensities to develop features analogous to
type 2 diabetes mellitus. To define chromosomal locations that control
these characteristics, Seldin et al. (1994) studied recombinant inbred
strains from diabetes-prone C57BL/6J and diabetes-resistant A/J strains.
Hyperglycemia correlated with the marker D7Mit25 on mouse chromosome 7.
This putative susceptibility locus is consistent with that of the
glycogen synthase gene, which was implicated by Groop et al. (1993) in
the pathogenesis of type 2 diabetes in the human. Seldin et al. (1994)
found that fractional glycogen synthase activity in isolated muscle was
significantly lower in normal B/6J diabetes-prone mice than in normal
diabetes-resistant A/J mice, a finding similar to that reported in
relatives of human patients with type 2 diabetes.
Pederson et al. (2004) found that 90% of Gys1 -/- mouse pups died
without taking a breath due to failure of the lungs to inflate.
Examination of Gys1 -/- embryos at 14.5 days postcoitum revealed venous
and pulmonary congestion, severely hemorrhagic livers, and abnormal
heart morphology, including thin ventricular walls resulting from
decreased cell proliferation. Gys1 -/- mice that survived to adulthood
had normal systolic blood pressure, heart rate, and electrocardiogram
and no gross heart abnormalities, although there was a trend toward
larger left ventricular mass, and the hearts of older males showed
significant fibrosis. Biochemical analysis of skeletal muscle and heart
of Gys1 -/- mice revealed the lack of glycogen; heterozygotes had
glycogen levels that tended to be lower than those of wildtype mice.
Polysaccharide storage myopathy (PSSM) is a glycogenosis in horses
characterized by abnormal glycogen accumulation in skeletal muscle and
muscle damage with exertion. In PSSM-affected horses, McCue et al.
(2008) identified a G-to-A change in exon 6 of the Gys1 gene, resulting
in an arg309-to-his (R309H) substitution. R309 is conserved in human
GYS1 and lies in a region that shares extensive identity with human
GYS1. Functional analysis demonstrated elevated glycogen synthase
activity in PSSM horses, indicating that R309H is a gain-of-function
mutation.
*FIELD* AV
.0001
GLYCOGEN STORAGE DISEASE 0, MUSCLE
GYS1, ARG462TER
In 3 sibs with muscle glycogen storage disease 0 (611556), the offspring
of consanguineous parents of Syrian origin, Kollberg et al. (2007)
detected a 1384C-T transition in exon 11 of the GYS1 gene, which changed
CGA, coding for arginine, to a TGA terminal signal. This premature stop
codon was predicted to result in truncation of muscle glycogen synthase
at amino acid residue 462 (R462X). Thus, the part of the enzyme
harboring the active site was predicted to be lost.
*FIELD* RF
1. Browner, M. F.; Nakano, K.; Bang, A. G.; Fletterick, R. J.: Human
muscle glycogen synthase cDNA sequence: a negatively charged protein
with an asymmetric charge distribution. Proc. Nat. Acad. Sci. 86:
1443-1447, 1989.
2. Groop, L. C.; Kankuri, M.; Schalin-Jantti, C.; Ekstrand, A.; Nikula-Ijas,
P.; Widen, E.; Kuismanen, E.; Eriksson, J.; Franssila-Kallunki, A.;
Saloranta, C.; Koskimies, S.: Association between polymorphism of
the glycogen synthase gene and non-insulin-dependent diabetes mellitus. New
Eng. J. Med. 328: 10-14, 1993. Note: Erratum: New Eng. J. Med. 328:
1136 only, 1993.
3. Huang, X.; Vaag, A.; Hansson, M.; Weng, J.; Laurila, E.; Groop,
L.: Impaired insulin-stimulated expression of the glycogen synthase
gene in skeletal muscle of type 2 diabetic patients is acquired rather
than inherited. J. Clin. Endocr. Metab. 85: 1584-1590, 2000.
4. Kadowaki, T.; Kadowaki, H.; Yazaki, Y.: Polymorphism of the glycogen
synthase gene and non-insulin-dependent diabetes mellitus. (Letter) New
Eng. J. Med. 328: 1569, 1993.
5. Kollberg, G.; Tulinius, M.; Gilljam, T.; Ostman-Smith, I.; Forsander,
G.; Jotorp, P.; Oldfors, A.; Holme, E.: Cardiomyopathy and exercise
intolerance in muscle glycogen storage disease 0. New Eng. J. Med. 357:
1507-1514, 2007.
6. Lehto, M.; Stoffel, M.; Groop, L.; Espinosa, R., III; Le Beau,
M. M.; Bell, G. I.: Assignment of the gene encoding glycogen synthase
(GYS) to human chromosome 19, band q13.3. Genomics 15: 460-461,
1993.
7. McCue, M. E.; Valberg, S. J.; Miller, M. B.; Wade, C.; DiMauro,
S.; Akman, H. O.; Mickelson, J. R.: Glycogen synthase (GYS1) mutation
causes a novel skeletal muscle glycogenosis. Genomics 91: 458-466,
2008.
8. Orho-Melander, M.; Almgren, P.; Kanninen, T.; Forsblom, C.; Groop,
L. C.: A paired-sibling analysis of the XbaI polymorphism in the
muscle glycogen synthase gene. Diabetologia 42: 1138-1145, 1999.
9. Pederson, B. A.; Chen, H.; Schroeder, J. M.; Shou, W.; DePaoli-Roach,
A. A.; Roach, P. J.: Abnormal cardiac development in the absence
of heart glycogen. Molec. Cell. Biol. 24: 7179-7187, 2004.
10. Pederson, B. A.; Chen, H.; Schroeder, J. M.; Shou, W.; DePaoli-Roach,
A. A.; Roach, P. J.: Abnormal cardiac development in the absence
of heart glycogen. Molec. Cell. Biol. 24: 7179-7187, 2004.
11. Pederson, B. A.; Cope, C. R.; Schroeder, J. M.; Smith, M. W.;
Irimia, J. M.; Thurberg, B. L.; DePaoli-Roach, A. A.; Roach, P. J.
: Exercise capacity of mice genetically lacking muscle glycogen synthase:
in mice, muscle glycogen is not essential for exercise. J. Biol.
Chem. 280: 17260-17265, 2005.
12. Pederson, B. A.; Schroeder, J. M.; Parker, G. E.; Smith, M. W.;
DePaoli-Roach, A. A.; Roach, P. J.: Glucose metabolism in mice lacking
muscle glycogen synthase. Diabetes 54: 3466-3473, 2005.
13. Seldin, M. F.; Mott, D.; Bhat, D.; Petro, A.; Kuhn, C. M.; Kingsmore,
S. F.; Bogardus, C.; Opara, E.; Feinglos, M. N.; Surwit, R. S.: Glycogen
synthase: a putative locus for diet-induced hyperglycemia. J. Clin.
Invest. 94: 269-276, 1994.
14. Zouali, H.; Velho, G.; Froguel, P.: Polymorphism of the glycogen
synthase gene and non-insulin-dependent diabetes mellitus. (Letter) New
Eng. J. Med. 328: 1568, 1993.
*FIELD* CN
Patricia A. Hartz - updated: 6/6/2008
Patricia A. Hartz - updated: 11/30/2007
Marla J. F. O'Neill - updated: 10/29/2007
Victor A. McKusick - updated: 10/16/2007
John A. Phillips, III - updated: 11/16/2000
*FIELD* CD
Victor A. McKusick: 9/11/1989
*FIELD* ED
carol: 04/12/2013
mgross: 6/11/2008
terry: 6/6/2008
carol: 12/4/2007
mgross: 12/4/2007
terry: 11/30/2007
wwang: 10/29/2007
alopez: 10/26/2007
terry: 10/16/2007
alopez: 1/12/2001
terry: 11/16/2000
terry: 11/6/1996
terry: 6/3/1996
terry: 8/26/1994
warfield: 4/20/1994
carol: 2/16/1994
carol: 6/22/1993
carol: 4/8/1993
carol: 3/18/1993
MIM
611556
*RECORD*
*FIELD* NO
611556
*FIELD* TI
#611556 GLYCOGEN STORAGE DISEASE 0, MUSCLE
;;GSD 0b; GSD0b;;
MUSCLE GLYCOGEN STORAGE DISEASE 0;;
read moreMUSCLE GLYCOGEN SYNTHASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder is caused by mutation in the gene encoding muscle glycogen
synthase (GYS1; 138570).
CLINICAL FEATURES
Among the offspring of consanguineous parents of Syrian origin, Kollberg
et al. (2007) described cardiomyopathy and exercise intolerance
associated with complete absence of muscle glycogen. The oldest brother
developed normally until the age of 4 years, when he had an episode of
tonic-clonic seizures. At the age of 10.5 years, while playing outside
his school, he suddenly collapsed as the result of cardiac arrest. At
autopsy, the heart weighed 200 g (normal range, 139 to 178). The left
ventricular wall was thickened. The cause of death was listed as
hypertrophic cardiomyopathy. Two years later, an 11-year-old brother was
investigated. After the age of 6 years, he had been unable to keep up
with the physical activity of his peers and had muscle symptoms similar
to those of patient 1. He likewise had signs of hypertrophic
cardiomyopathy and an abnormal heart rate and blood pressure while
exercising. Low normal IQ was reported. A 2-year-old sister had no
clinical symptoms and had normal psychomotor development, however,
cardiac exam indicated cardiac involvement ('subtly impaired systolic
function at rest'). In muscle biopsy specimens obtained from the 2
younger sibs there was lack of glycogen, predominance of oxidative
fibers, and mitochondrial proliferation. Glucose tolerance was normal.
MOLECULAR GENETICS
In 3 sibs with muscle and heart glycogen deficiency, Kollberg et al.
(2007) found a premature termination mutation in the muscle glycogen
synthase gene (R462X; 138570.0001). Several findings in the patients
reported by Kollberg et al. (2007) were in accord with the findings in
muscle glycogen synthase knockout mice: increased cardiac mass, absence
of muscle glycogen, predominance of oxidative muscle fibers, and
normal-to-improved glucose clearance (Pederson et al., 2004, 2005, 2005)
The first patient had epilepsy; whether this was coincidental to the
glycogen storage disease was not clear. Glycogen is stored in the normal
brain, and one hypothesis is that the primary function of the cerebral
glycogen pool is to help provide energy to support rapid glutamate
neurotransmitter clearance by astrocytes (Shulman et al., 2001).
NOMENCLATURE
Kollberg et al. (2007) suggested that the entity they described be
termed muscle glycogen storage disease 0 in analogy with the disease
caused by liver glycogen synthase deficiency (240600).
*FIELD* RF
1. Kollberg, G.; Tulinius, M.; Gilljam, T.; Ostman-Smith, I.; Forsander,
G.; Jotorp, P.; Oldfors, A.; Holme, E.: Cardiomyopathy and exercise
intolerance in muscle glycogen storage disease 0. New Eng. J. Med. 357:
1507-1514, 2007.
2. Pederson, B. A.; Chen, H.; Schroeder, J. M.; Shou, W.; DePaoli-Roach,
A. A.; Roach, P. J.: Abnormal cardiac development in the absence
of heart glycogen. Molec. Cell. Biol. 24: 7179-7187, 2004.
3. Pederson, B. A.; Cope, C. R.; Schroeder, J. M.; Smith, M. W.; Irimia,
J. M.; Thurberg, B. L.; DePaoli-Roach, A. A.; Roach, P. J.: Exercise
capacity of mice genetically lacking muscle glycogen synthase: in
mice, muscle glycogen is not essential for exercise. J. Biol. Chem. 280:
17260-17265, 2005.
4. Pederson, B. A.; Schroeder, J. M.; Parker, G. E.; Smith, M. W.;
DePaoli-Roach, A. A.; Roach, P. J.: Glucose metabolism in mice lacking
muscle glycogen synthase. Diabetes 54: 3466-3473, 2005.
5. Shulman, R. G.; Hyder, F.; Rothman, D. L.: Cerebral energetics
and the glycogen shunt: neurochemical basis of functional imaging. Proc.
Nat. Acad. Sci. 98: 6417-6422, 2001.
*FIELD* CD
Victor A. McKusick: 10/26/2007
*FIELD* ED
joanna: 09/06/2012
wwang: 3/19/2008
alopez: 10/26/2007
*RECORD*
*FIELD* NO
611556
*FIELD* TI
#611556 GLYCOGEN STORAGE DISEASE 0, MUSCLE
;;GSD 0b; GSD0b;;
MUSCLE GLYCOGEN STORAGE DISEASE 0;;
read moreMUSCLE GLYCOGEN SYNTHASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder is caused by mutation in the gene encoding muscle glycogen
synthase (GYS1; 138570).
CLINICAL FEATURES
Among the offspring of consanguineous parents of Syrian origin, Kollberg
et al. (2007) described cardiomyopathy and exercise intolerance
associated with complete absence of muscle glycogen. The oldest brother
developed normally until the age of 4 years, when he had an episode of
tonic-clonic seizures. At the age of 10.5 years, while playing outside
his school, he suddenly collapsed as the result of cardiac arrest. At
autopsy, the heart weighed 200 g (normal range, 139 to 178). The left
ventricular wall was thickened. The cause of death was listed as
hypertrophic cardiomyopathy. Two years later, an 11-year-old brother was
investigated. After the age of 6 years, he had been unable to keep up
with the physical activity of his peers and had muscle symptoms similar
to those of patient 1. He likewise had signs of hypertrophic
cardiomyopathy and an abnormal heart rate and blood pressure while
exercising. Low normal IQ was reported. A 2-year-old sister had no
clinical symptoms and had normal psychomotor development, however,
cardiac exam indicated cardiac involvement ('subtly impaired systolic
function at rest'). In muscle biopsy specimens obtained from the 2
younger sibs there was lack of glycogen, predominance of oxidative
fibers, and mitochondrial proliferation. Glucose tolerance was normal.
MOLECULAR GENETICS
In 3 sibs with muscle and heart glycogen deficiency, Kollberg et al.
(2007) found a premature termination mutation in the muscle glycogen
synthase gene (R462X; 138570.0001). Several findings in the patients
reported by Kollberg et al. (2007) were in accord with the findings in
muscle glycogen synthase knockout mice: increased cardiac mass, absence
of muscle glycogen, predominance of oxidative muscle fibers, and
normal-to-improved glucose clearance (Pederson et al., 2004, 2005, 2005)
The first patient had epilepsy; whether this was coincidental to the
glycogen storage disease was not clear. Glycogen is stored in the normal
brain, and one hypothesis is that the primary function of the cerebral
glycogen pool is to help provide energy to support rapid glutamate
neurotransmitter clearance by astrocytes (Shulman et al., 2001).
NOMENCLATURE
Kollberg et al. (2007) suggested that the entity they described be
termed muscle glycogen storage disease 0 in analogy with the disease
caused by liver glycogen synthase deficiency (240600).
*FIELD* RF
1. Kollberg, G.; Tulinius, M.; Gilljam, T.; Ostman-Smith, I.; Forsander,
G.; Jotorp, P.; Oldfors, A.; Holme, E.: Cardiomyopathy and exercise
intolerance in muscle glycogen storage disease 0. New Eng. J. Med. 357:
1507-1514, 2007.
2. Pederson, B. A.; Chen, H.; Schroeder, J. M.; Shou, W.; DePaoli-Roach,
A. A.; Roach, P. J.: Abnormal cardiac development in the absence
of heart glycogen. Molec. Cell. Biol. 24: 7179-7187, 2004.
3. Pederson, B. A.; Cope, C. R.; Schroeder, J. M.; Smith, M. W.; Irimia,
J. M.; Thurberg, B. L.; DePaoli-Roach, A. A.; Roach, P. J.: Exercise
capacity of mice genetically lacking muscle glycogen synthase: in
mice, muscle glycogen is not essential for exercise. J. Biol. Chem. 280:
17260-17265, 2005.
4. Pederson, B. A.; Schroeder, J. M.; Parker, G. E.; Smith, M. W.;
DePaoli-Roach, A. A.; Roach, P. J.: Glucose metabolism in mice lacking
muscle glycogen synthase. Diabetes 54: 3466-3473, 2005.
5. Shulman, R. G.; Hyder, F.; Rothman, D. L.: Cerebral energetics
and the glycogen shunt: neurochemical basis of functional imaging. Proc.
Nat. Acad. Sci. 98: 6417-6422, 2001.
*FIELD* CD
Victor A. McKusick: 10/26/2007
*FIELD* ED
joanna: 09/06/2012
wwang: 3/19/2008
alopez: 10/26/2007