RBCC Red Blood Cell Collection

AGL (GDE) [Confidence: low (only semi-automatic identification from reviews)]
Glycogen debranching enzyme (Glycogen debrancher; 4-alpha-glucanotransferase; 2.4.1.25; Oligo-1,4-1,4-glucantransferase; Amylo-alpha-1,6-glucosidase; Amylo-1,6-glucosidase; 3.2.1.33; Dextrin 6-alpha-D-glucosidase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P35573
ID GDE_HUMAN Reviewed; 1532 AA.
AC P35573; A6NCX7; A6NEK2; D3DT51; P78354; P78544; Q59H92; Q6AZ90;
read moreAC Q9UF08;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 3.
DT 22-JAN-2014, entry version 135.
DE RecName: Full=Glycogen debranching enzyme;
DE AltName: Full=Glycogen debrancher;
DE Includes:
DE RecName: Full=4-alpha-glucanotransferase;
DE EC=2.4.1.25;
DE AltName: Full=Oligo-1,4-1,4-glucantransferase;
DE Includes:
DE RecName: Full=Amylo-alpha-1,6-glucosidase;
DE Short=Amylo-1,6-glucosidase;
DE EC=3.2.1.33;
DE AltName: Full=Dextrin 6-alpha-D-glucosidase;
GN Name=AGL; Synonyms=GDE;
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], AND PARTIAL PROTEIN SEQUENCE (ISOFORM 5).
RC TISSUE=Muscle;
RX PubMed=1374391;
RA Yang B.-Z., Ding J.-H., Enghild J.J., Bao Y., Chen Y.-T.;
RT "Molecular cloning and nucleotide sequence of cDNA encoding human
RT muscle glycogen debranching enzyme.";
RL J. Biol. Chem. 267:9294-9299(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE SPLICING.
RX PubMed=8954797; DOI=10.1006/geno.1996.0611;
RA Bao Y., Dawson T.L. Jr., Chen Y.-T.;
RT "Human glycogen debranching enzyme gene (AGL): complete structural
RT organization and characterization of the 5' flanking region.";
RL Genomics 38:155-165(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE SPLICING.
RC TISSUE=Liver;
RX PubMed=9332391; DOI=10.1016/S0378-1119(97)00291-6;
RA Bao Y., Yang B.-Z., Dawson T.L. Jr., Chen Y.-T.;
RT "Isolation and nucleotide sequence of human liver glycogen debranching
RT enzyme mRNA: identification of multiple tissue-specific isoforms.";
RL Gene 197:389-398(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1), AND VARIANTS.
RX PubMed=10982190; DOI=10.1007/s004390051017;
RA Okubo M., Horinishi A., Takeuchi M., Suzuki Y., Sakura N.,
RA Hasegawa Y., Igarashi T., Goto K., Tahara H., Uchimoto S., Omichi K.,
RA Kanno H., Hayasaka K., Murase T.;
RT "Heterogeneous mutations in the glycogen-debranching enzyme gene are
RT responsible for glycogen storage disease type IIIa in Japan.";
RL Hum. Genet. 106:108-115(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [9]
RP UBIQUITINATION, CHARACTERIZATION OF VARIANT GSD3 ARG-1448, INTERACTION
RP WITH NHLRC1, AND SUBCELLULAR LOCATION.
RX PubMed=17908927; DOI=10.1101/gad.1553207;
RA Cheng A., Zhang M., Gentry M.S., Worby C.A., Dixon J.E., Saltiel A.R.;
RT "A role for AGL ubiquitination in the glycogen storage disorders of
RT Lafora and Cori's disease.";
RL Genes Dev. 21:2399-2409(2007).
RN [10]
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 [11]
RP VARIANT GSD3 ARG-1448, AND VARIANT ARG-1115.
RX PubMed=10571954;
RX DOI=10.1002/(SICI)1098-1004(199912)14:6<542::AID-HUMU15>3.0.CO;2-0;
RA Okubo M., Kanda F., Horinishi A., Takahashi K., Okuda S., Chihara K.,
RA Murase T.;
RT "Glycogen storage disease type IIIa: first report of a causative
RT missense mutation (G1448R) of the glycogen debranching enzyme gene
RT found in a homozygous patient.";
RL Hum. Mutat. 14:542-543(1999).
CC -!- FUNCTION: Multifunctional enzyme acting as 1,4-alpha-D-glucan:1,4-
CC alpha-D-glucan 4-alpha-D-glycosyltransferase and amylo-1,6-
CC glucosidase in glycogen degradation.
CC -!- CATALYTIC ACTIVITY: Transfers a segment of a (1->4)-alpha-D-glucan
CC to a new position in an acceptor, which may be glucose or a
CC (1->4)-alpha-D-glucan.
CC -!- CATALYTIC ACTIVITY: Hydrolysis of (1->6)-alpha-D-glucosidic branch
CC linkages in glycogen phosphorylase limit dextrin.
CC -!- SUBUNIT: Monomer. Interacts with NHLRC1/malin.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=Under glycogenolytic
CC conditions localizes to the nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=2, 3, 4;
CC IsoId=P35573-1; Sequence=Displayed;
CC Note=The products of the mRNAs termed isoforms 1 to 4 are
CC identical;
CC Name=5;
CC IsoId=P35573-2; Sequence=VSP_004270;
CC Name=6;
CC IsoId=P35573-3; Sequence=VSP_004271;
CC Note=Ref.2 (AAB48470) sequence is in conflict in position:
CC 4:I->L;
CC -!- TISSUE SPECIFICITY: Liver, kidney and lymphoblastoid cells express
CC predominantly isoform 1; whereas muscle and heart express not only
CC isoform 1, but also muscle-specific isoform mRNAs (isoforms 2, 3
CC and 4). Isoforms 5 and 6 are present in both liver and muscle.
CC -!- PTM: The N-terminus is blocked.
CC -!- PTM: Ubiquitinated.
CC -!- DISEASE: Glycogen storage disease 3 (GSD3) [MIM:232400]: A
CC metabolic disorder associated with an accumulation of abnormal
CC glycogen with short outer chains. It is clinically characterized
CC by hepatomegaly, hypoglycemia, short stature, and variable
CC myopathy. Glycogen storage disease type 3 includes different
CC forms: GSD type 3A patients lack glycogen debrancher enzyme
CC activity in both liver and muscle, while GSD type 3B patients are
CC enzyme-deficient in liver only. In rare cases, selective loss of
CC only 1 of the 2 debranching activities, glucosidase or
CC transferase, results in GSD type 3C or type 3D, respectively.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the glycogen debranching enzyme family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD92104.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/AGL";
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DR EMBL; M85168; AAB41040.1; -; mRNA.
DR EMBL; U84007; AAB48466.1; -; mRNA.
DR EMBL; U84008; AAB48467.1; -; mRNA.
DR EMBL; U84009; AAB48468.1; -; mRNA.
DR EMBL; U84010; AAB48469.1; -; mRNA.
DR EMBL; U84011; AAB48470.1; -; mRNA.
DR EMBL; AB035443; BAA88405.1; -; Genomic_DNA.
DR EMBL; AB208867; BAD92104.1; ALT_INIT; mRNA.
DR EMBL; AC096949; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471097; EAW72985.1; -; Genomic_DNA.
DR EMBL; CH471097; EAW72982.1; -; Genomic_DNA.
DR EMBL; CH471097; EAW72983.1; -; Genomic_DNA.
DR EMBL; CH471097; EAW72987.1; -; Genomic_DNA.
DR EMBL; BC078663; AAH78663.1; -; mRNA.
DR RefSeq; NP_000019.2; NM_000028.2.
DR RefSeq; NP_000633.2; NM_000642.2.
DR RefSeq; NP_000634.2; NM_000643.2.
DR RefSeq; NP_000635.2; NM_000644.2.
DR RefSeq; NP_000636.2; NM_000645.2.
DR RefSeq; NP_000637.2; NM_000646.2.
DR RefSeq; XP_005270614.1; XM_005270557.1.
DR UniGene; Hs.904; -.
DR ProteinModelPortal; P35573; -.
DR SMR; P35573; 138-230.
DR IntAct; P35573; 9.
DR MINT; MINT-2802883; -.
DR STRING; 9606.ENSP00000294724; -.
DR BindingDB; P35573; -.
DR ChEMBL; CHEMBL5272; -.
DR CAZy; GH13; Glycoside Hydrolase Family 13.
DR PhosphoSite; P35573; -.
DR DMDM; 116242491; -.
DR PaxDb; P35573; -.
DR PRIDE; P35573; -.
DR Ensembl; ENST00000294724; ENSP00000294724; ENSG00000162688.
DR Ensembl; ENST00000361302; ENSP00000354971; ENSG00000162688.
DR Ensembl; ENST00000361522; ENSP00000354635; ENSG00000162688.
DR Ensembl; ENST00000361915; ENSP00000355106; ENSG00000162688.
DR Ensembl; ENST00000370161; ENSP00000359180; ENSG00000162688.
DR Ensembl; ENST00000370163; ENSP00000359182; ENSG00000162688.
DR Ensembl; ENST00000370165; ENSP00000359184; ENSG00000162688.
DR GeneID; 178; -.
DR KEGG; hsa:178; -.
DR UCSC; uc001dsi.1; human.
DR CTD; 178; -.
DR GeneCards; GC01P100315; -.
DR HGNC; HGNC:321; AGL.
DR HPA; HPA028498; -.
DR MIM; 232400; phenotype.
DR MIM; 610860; gene.
DR neXtProt; NX_P35573; -.
DR Orphanet; 366; Glycogen storage disease due to glycogen debranching enzyme deficiency.
DR PharmGKB; PA24618; -.
DR eggNOG; COG3408; -.
DR HOVERGEN; HBG005824; -.
DR InParanoid; P35573; -.
DR KO; K01196; -.
DR OMA; VGILRNH; -.
DR OrthoDB; EOG7C5M7F; -.
DR BioCyc; MetaCyc:HS08717-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR GeneWiki; Glycogen_debranching_enzyme; -.
DR GenomeRNAi; 178; -.
DR NextBio; 722; -.
DR PRO; PR:P35573; -.
DR ArrayExpress; P35573; -.
DR Bgee; P35573; -.
DR CleanEx; HS_AGL; -.
DR Genevestigator; P35573; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016234; C:inclusion body; IEA:Ensembl.
DR GO; GO:0043033; C:isoamylase complex; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0016529; C:sarcoplasmic reticulum; IEA:Ensembl.
DR GO; GO:0004134; F:4-alpha-glucanotransferase activity; IBA:RefGenome.
DR GO; GO:0004135; F:amylo-alpha-1,6-glucosidase activity; IBA:RefGenome.
DR GO; GO:0030247; F:polysaccharide binding; IEA:Ensembl.
DR GO; GO:0006006; P:glucose metabolic process; TAS:Reactome.
DR GO; GO:0005978; P:glycogen biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0005980; P:glycogen catabolic process; IBA:RefGenome.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 3.20.20.80; -; 3.
DR InterPro; IPR008928; 6-hairpin_glycosidase-like.
DR InterPro; IPR010401; AGL/Gdb1.
DR InterPro; IPR013781; Glyco_hydro_catalytic_dom.
DR InterPro; IPR006421; Glycogen_debranch_met.
DR InterPro; IPR017853; Glycoside_hydrolase_SF.
DR PANTHER; PTHR10569; PTHR10569; 1.
DR Pfam; PF06202; GDE_C; 1.
DR SUPFAM; SSF48208; SSF48208; 2.
DR SUPFAM; SSF51445; SSF51445; 2.
DR TIGRFAMs; TIGR01531; glyc_debranch; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Glycogen biosynthesis;
KW Glycogen storage disease; Glycosidase; Glycosyltransferase; Hydrolase;
KW Multifunctional enzyme; Polymorphism; Reference proteome; Transferase;
KW Ubl conjugation.
FT CHAIN 1 1532 Glycogen debranching enzyme.
FT /FTId=PRO_0000087450.
FT REGION 1 ? 4-alpha-glucanotransferase.
FT REGION ? 1532 Amylo-1,6-glucosidase.
FT ACT_SITE 526 526 By similarity.
FT ACT_SITE 529 529 By similarity.
FT ACT_SITE 627 627 By similarity.
FT VAR_SEQ 1 27 MGHSKQIRILLLNEMEKLEKTLFRLEQ -> MSLLTCAFYL
FT (in isoform 5).
FT /FTId=VSP_004270.
FT VAR_SEQ 1 27 MGHSKQIRILLLNEMEKLEKTLFRLEQ -> MAPILSINLF
FT I (in isoform 6).
FT /FTId=VSP_004271.
FT VARIANT 38 38 T -> A (in dbSNP:rs35278779).
FT /FTId=VAR_032084.
FT VARIANT 229 229 Q -> R (in dbSNP:rs17121403).
FT /FTId=VAR_028051.
FT VARIANT 387 387 R -> Q (in dbSNP:rs17121464).
FT /FTId=VAR_009621.
FT VARIANT 701 701 A -> S (in dbSNP:rs3736297).
FT /FTId=VAR_028052.
FT VARIANT 962 962 S -> C (in dbSNP:rs34714252).
FT /FTId=VAR_032085.
FT VARIANT 1067 1067 P -> S (in dbSNP:rs3753494).
FT /FTId=VAR_020389.
FT VARIANT 1115 1115 G -> R (in dbSNP:rs2230307).
FT /FTId=VAR_009230.
FT VARIANT 1144 1144 I -> N (in dbSNP:rs2230308).
FT /FTId=VAR_028053.
FT VARIANT 1207 1207 A -> T (in dbSNP:rs11807956).
FT /FTId=VAR_051010.
FT VARIANT 1253 1253 R -> H (in dbSNP:rs12043139).
FT /FTId=VAR_028054.
FT VARIANT 1343 1343 E -> K (in dbSNP:rs112795811).
FT /FTId=VAR_009622.
FT VARIANT 1448 1448 G -> R (in GSD3; deficient in ability to
FT bind glycogen; unstable due to enhanced
FT ubiquitination; forms aggresomes upon
FT proteasome impairment).
FT /FTId=VAR_009231.
FT VARIANT 1487 1487 R -> G (in dbSNP:rs12118058).
FT /FTId=VAR_028055.
FT CONFLICT 1398 1398 W -> G (in Ref. 1; AAB41040, 2; AAB48466/
FT AAB48467/AAB48468/AAB48469/AAB48470 and
FT 3).
SQ SEQUENCE 1532 AA; 174764 MW; 9BF1BCC43B7904D3 CRC64;
MGHSKQIRIL LLNEMEKLEK TLFRLEQGYE LQFRLGPTLQ GKAVTVYTNY PFPGETFNRE
KFRSLDWENP TEREDDSDKY CKLNLQQSGS FQYYFLQGNE KSGGGYIVVD PILRVGADNH
VLPLDCVTLQ TFLAKCLGPF DEWESRLRVA KESGYNMIHF TPLQTLGLSR SCYSLANQLE
LNPDFSRPNR KYTWNDVGQL VEKLKKEWNV ICITDVVYNH TAANSKWIQE HPECAYNLVN
SPHLKPAWVL DRALWRFSCD VAEGKYKEKG IPALIENDHH MNSIRKIIWE DIFPKLKLWE
FFQVDVNKAV EQFRRLLTQE NRRVTKSDPN QHLTIIQDPE YRRFGCTVDM NIALTTFIPH
DKGPAAIEEC CNWFHKRMEE LNSEKHRLIN YHQEQAVNCL LGNVFYERLA GHGPKLGPVT
RKHPLVTRYF TFPFEEIDFS MEESMIHLPN KACFLMAHNG WVMGDDPLRN FAEPGSEVYL
RRELICWGDS VKLRYGNKPE DCPYLWAHMK KYTEITATYF QGVRLDNCHS TPLHVAEYML
DAARNLQPNL YVVAELFTGS EDLDNVFVTR LGISSLIREA MSAYNSHEEG RLVYRYGGEP
VGSFVQPCLR PLMPAIAHAL FMDITHDNEC PIVHRSAYDA LPSTTIVSMA CCASGSTRGY
DELVPHQISV VSEERFYTKW NPEALPSNTG EVNFQSGIIA ARCAISKLHQ ELGAKGFIQV
YVDQVDEDIV AVTRHSPSIH QSVVAVSRTA FRNPKTSFYS KEVPQMCIPG KIEEVVLEAR
TIERNTKPYR KDENSINGTP DITVEIREHI QLNESKIVKQ AGVATKGPNE YIQEIEFENL
SPGSVIIFRV SLDPHAQVAV GILRNHLTQF SPHFKSGSLA VDNADPILKI PFASLASRLT
LAELNQILYR CESEEKEDGG GCYDIPNWSA LKYAGLQGLM SVLAEIRPKN DLGHPFCNNL
RSGDWMIDYV SNRLISRSGT IAEVGKWLQA MFFYLKQIPR YLIPCYFDAI LIGAYTTLLD
TAWKQMSSFV QNGSTFVKHL SLGSVQLCGV GKFPSLPILS PALMDVPYRL NEITKEKEQC
CVSLAAGLPH FSSGIFRCWG RDTFIALRGI LLITGRYVEA RNIILAFAGT LRHGLIPNLL
GEGIYARYNC RDAVWWWLQC IQDYCKMVPN GLDILKCPVS RMYPTDDSAP LPAGTLDQPL
FEVIQEAMQK HMQGIQFRER NAGPQIDRNM KDEGFNITAG VDEETGFVYG GNRFNCGTWM
DKMGESDRAR NRGIPATPRD GSAVEIVGLS KSAVRWLLEL SKKNIFPYHE VTVKRHGKAI
KVSYDEWNRK IQDNFEKLFH VSEDPSDLNE KHPNLVHKRG IYKDSYGASS PWCDYQLRPN
FTIAMVVAPE LFTTEKAWKA LEIAEKKLLG PLGMKTLDPD DMVYCGIYDN ALDNDNYNLA
KGFNYHQGPE WLWPIGYFLR AKLYFSRLMG PETTAKTIVL VKNVLSRHYV HLERSPWKGL
PELTNENAQY CPFSCETQAW SIATILETLY DL
//

MIM 232400
*RECORD*
*FIELD* NO
232400
*FIELD* TI
#232400 GLYCOGEN STORAGE DISEASE III
;;GSD III; GSD3;;
FORBES DISEASE;;
CORI DISEASE;;
read moreLIMIT DEXTRINOSIS;;
AMYLO-1,6-GLUCOSIDASE DEFICIENCY;;
AGL DEFICIENCY;;
GLYCOGEN DEBRANCHER DEFICIENCY;;
GDE DEFICIENCY
GLYCOGEN STORAGE DISEASE IIIa, INCLUDED; GSD IIIa, INCLUDED;;
GLYCOGEN STORAGE DISEASE IIIb, INCLUDED; GSD IIIb, INCLUDED;;
GLYCOGEN STORAGE DISEASE IIIc, INCLUDED; GSD IIIc, INCLUDED;;
GLYCOGEN STORAGE DISEASE IIId, INCLUDED; GSD IIId, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because glycogen storage
disease III (GSD3) is caused by homozygous or compound heterozygous
mutation in the gene encoding the glycogen debrancher enzyme (AGL;
610860) on chromosome 1p21.

DESCRIPTION

Glycogen storage disease III is an autosomal recessive metabolic
disorder caused by deficiency of the glycogen debrancher enzyme and
associated with an accumulation of abnormal glycogen with short outer
chains. Most patients are enzyme-deficient in both liver and muscle
(IIIa), but about 15% are enzyme-deficient in liver only (IIIb) (Shen et
al., 1996). These subtypes have been explained by differences in tissue
expression of the deficient enzyme (Endo et al., 2006). In rare cases,
selective loss of only 1 of the 2 debranching activities, glucosidase or
transferase, results in type IIIc or IIId, respectively. (Van Hoof and
Hers, 1967; Ding et al., 1990).

Clinically, patients with GSD III present in infancy or early childhood
with hepatomegaly, hypoglycemia, and growth retardation. Muscle weakness
in those with IIIa is minimal in childhood but can become more severe in
adults; some patients develop cardiomyopathy (Shen et al., 1996).

Lucchiari et al. (2007) provided a review of GSD III.

CLINICAL FEATURES

Brunberg et al. (1971) reported an adult with GSD III who had diffuse
muscle weakness and wasting. DiMauro et al. (1979) reported 5 adult
patients with adult-onset, slowly progressive muscle weakness associated
with debrancher enzyme deficiency. Two patients had distal muscle
wasting, 3 had hepatomegaly, and 2 had congestive heart failure.
Electromyography showed a mixed pattern with abundant fibrillations, and
serum creatine kinase was increased 5- to 45-fold. Skeletal muscle
biopsy showed a vacuolar myopathy with increased glycogen content.
DiMauro et al. (1979) suggested that debrancher deficiency myopathy may
not be rare and should be considered in the differential diagnosis of
adult-onset hereditary myopathies.

Fellows et al. (1983) reported 2 unrelated adults with GSD III who
presented with liver disease, one of whom developed fatal cirrhosis.
Both had hepatomegaly since childhood. Histology showed unusual hepatic
vacuolation.

In Israel, Moses et al. (1989) performed cardiologic studies on 20
patients, aged 3 to 30 years, with enzymatically proven GSD IIIa.
Seventeen patients showed subclinical evidence of cardiac involvement in
the form of ventricular hypertrophy on ECG; 13 of 16 patients in whom an
echocardiographic examination was performed had abnormal findings. Only
2 had cardiomegaly on x-ray. Moses et al. (1989) described in detail the
findings in a 25-year-old female with clinically evident cardiomyopathy.

Momoi et al. (1992) reviewed the case histories of 19 Japanese patients
with GSD IIIa who developed muscular symptoms at various ages. They
divided the patients into 4 groups: one with childhood onset of both
muscle weakness and hepatic disorders; one with onset of muscular
symptoms in adulthood while liver symptoms started in childhood; one
with muscle weakness starting in adulthood long after liver symptoms in
childhood had disappeared; and one with only muscle symptoms as adults
without any sign or history of liver dysfunction after childhood.

Coleman et al. (1992) studied 13 patients with GSD III followed from
infancy. Activities of serum aspartate and alanine transaminases,
lactate dehydrogenase, and alkaline phosphatase were markedly elevated
during infancy. The serum enzyme activities declined around puberty
concomitantly with a decrease in liver size. Although periportal
fibrosis and micronodular cirrhosis indicated the presence of
hepatocellular damage during childhood, the decline in serum enzyme
activities with age and the absence of overt hepatic dysfunction
suggested to the authors that the fibrotic process may not always
progress.

Markowitz et al. (1993) described a white man in whom the diagnosis of
GSD III was made on the basis of open liver biopsy at the age of 1 year.
At the age of 31 years, he presented with variceal hemorrhage secondary
to hepatic cirrhosis. No other cause of the cirrhosis was found, other
than deficiency of debranching enzyme, which was documented both in
liver and skeletal muscle.

In a multicenter study in the United States and Canada, Talente et al.
(1994) identified 9 patients with GSD III who were 18 years of age or
older. Increased creatine kinase activity was observed in 6 patients; 4
had myopathy and cardiomyopathy. One of the patients reported in detail
was a 55-year-old man who owned and managed a small business. At age 30,
he had gradual onset of weakness in his hands and feet. The distal
muscles atrophied, and weakness progressed to include the limb-girdle
region.

Hadjigeorgiou et al. (1999) reported 4 adult Italian patients with GSD
IIIa confirmed by molecular analysis. All patients had a history of
infantile hepatomegaly followed by myopathy in their twenties. AGL
activity and protein were almost absent in muscle specimens. A
remarkably severe clinical history was noted in 1 patient, who underwent
liver transplantation at 23 years of age and developed a proximal
myopathy and an obstructive hypertrophic cardiomyopathy by age 30 years.

In 7 patients with GSD III, Cleary et al. (2002) identified consistent
facial features including midface hypoplasia with a depressed nasal
bridge and a broad upturned nasal tip, indistinct philtral pillars, and
bow-shaped lips with a thin vermilion border. In addition, younger
patients had deep-set eyes. Several children had clinical problems such
as persistent otitis media or recurrent sinusitis. The similar features
in these patients suggested a distinct facial phenotype for this
disorder.

Schoser et al. (2008) reported a family with variable presentation of
GSD III. The 49-year-old female proband presented with hepatomegaly,
cardiomyopathy, and moderate progressive proximal limb myopathy. She
developed proximal muscle weakness at age 10 and signs and symptoms of
cardiomyopathy at age 30. She also had progressive hearing impairment
beginning at age 30. Skeletal muscle biopsy showed severe vacuolar
myopathy with PAS-positive glycogen storage material that altered the
contractile apparatus. Two brothers had died of severe infantile liver
cirrhosis, and a sister died with cardiomyopathy, hepatomegaly, and
myopathy at age 33. The proband was homozygous for a truncating mutation
in the AGL gene. Heterozygous family members had exercise-inducted
myalgia and weakness since their teens. Schoser et al. (2008) concluded
that, with the exception of early infantile fatal cirrhosis, patients
with GSD III may stay ambulatory until adulthood.

Aoyama et al. (2009) reported a 14-year-old Turkish girl with GSD type
IIIc, or isolated glucosidase deficiency, due to homozygosity for an AGL
mutation (R1147G; 610860.0014). She had mild hepatomegaly, but no
clinical muscle involvement or hypoglycemia. The authors stated that
this was the first molecular diagnosis in a patient with GSD IIIc.

- Clinical Variability

Ebermann et al. (2008) reported an 11-year-old boy, born of Egyptian
consanguineous parents, with a phenotype suggestive of Navajo
neurohepatopathy (MTDPS6; 256810) including short stature, frequent
painless fractures, bruises, and cuts, hepatomegaly with elevated liver
enzymes, corneal ulcerations, and mild hypotonia. His 22-month-old
sister had short stature, hepatomegaly, increased liver enzymes, and
hypotonia. A cousin had died at age 8 years from liver failure. After
genetic analysis excluded a mutation in the MPV17 gene (136960),
Ebermann et al. (2008) postulated 2 recessive diseases. Genomewide
linkage analysis and gene sequencing of the proband identified a
homozygous mutation in the AGL gene, consistent with glycogen storage
disease III, and a homozygous mutation in the SCN9A gene (603415),
consistent with congenital insensitivity to pain (CIPA; 243000). His
sister had the AGL mutation and GSD3 only. Ebermann et al. (2008)
emphasized that consanguineous matings increase the risk of homozygous
genotypes and recessive diseases, which may complicate genetic
counseling.

BIOCHEMICAL FEATURES

Rosenfeld et al. (1976) reported 5 patients with GSD III from the USSR.
All had hypoglycemia after an overnight fast. Liver glycogen was
increased and there was complete absence of liver AGL activity. Two
patients also had a decrease in liver phosphorylase (232700) activity,
and another had a decrease in glucose-6-phosphatase (613742) activity.

By immunoblot studies, Chen et al. (1987) found absence of the glycogen
debranching enzyme in liver and muscle samples from patients with GSD
III. Cross-reactive material was detected in liver and muscle samples
from patients with other types of glycogen storage disease, indicating
that absence of the debranching enzyme in liver and muscle is specific
for GSD III.

DIAGNOSIS

Shen et al. (1997) used 3 polymorphic markers within the AGL gene for
linkage analysis of GSD III and showed the potential use of these
markers for carrier detection and prenatal diagnosis.

MOLECULAR GENETICS

In 3 unrelated patients with GSD IIIb, Shen et al. (1996) identified
homozygous or compound heterozygous mutations in the AGL gene (see,
e.g., 610860.0002-610860.0004). One of the mutations (17delAG;
610860.0004) was found in 8 of 10 additional GSD IIIb patients.
Mutations in exon 3 were present in 12 of 13 GSD IIIb patients,
suggesting a specific association. In addition, the identification of
exon 3 mutations may have clinical significance because it can
distinguish GSD IIIb from IIIa. The 3 patients with GSD IIIb in whom
mutations were studied in detail were aged 25 years, 18 years, and 41
years; they had no clinical or laboratory evidence of myopathy or
cardiomyopathy.

Shen et al. (1997) identified a homozygous mutation in the AGL gene
(610860.0001) in a child with an unusually severe GSD IIIa phenotype.
Okubo et al. (2000) identified 7 different mutations in the AGL gene,
including 6 novel mutations, among 8 Japanese GSD IIIa patients from 7
families.

Shaiu et al. (2000) reported 2 frequent mutations, each of which was
found in homozygous state in multiple patients, and each of which was
associated with a subset of clinical phenotype in those patients with
that mutation. One mutation (IVS32-12A-G; 610860.0006) was identified in
homozygosity in a confirmed GSD IIIa Caucasian patient who presented
with mild clinical symptoms. This mutation had an allele frequency of
approximately 5.5% in GSD III patients tested. The other common mutation
(3964delT; 610860.0010) was identified in an African American patient
who had a severe phenotype and early onset of clinical symptoms. The
mutation was later identified in several other patients and was observed
at a frequency of approximately 6.7%. Together, these 2 mutations can
account for more than 12% of the molecular defects in GSD III patients.
Shaiu et al. (2000) also identified 6 additional mutations and reviewed
the nonmutation state.

Lucchiari et al. (2002) identified 7 novel mutations of the AGL gene in
patients with GSD IIIa in the Mediterranean area.

Endo et al. (2006) identified 9 different mutations in the AGL gene,
including 6 novel mutations, among 9 patients with GSD III. The patients
were from Germany, Canada, Afghanistan, Iran, and Turkey.

Aoyama et al. (2009) identified 10 different AGL mutations, including 8
novel mutations (see, e.g., 610860.0014 and 610860.0015), in 23 Turkish
patients with GSD III. No genotype/phenotype correlations were observed.

POPULATION GENETICS

In Israel, 73% of glycogen storage disease was of type III. All cases
were non-Ashkenazim, being mainly of North African extraction, in which
group the incidence was 1 in 5,420 (Levin et al., 1967).

The overall incidence of GSD III is about 1 in 100,000 live births in
the U.S.; however, it is unusually frequent among North African Jewish
individuals in Israel (1 in 5,400 with a carrier frequency of 1 in 35)
(Parvari et al., 1997).

Cohn et al. (1975) reported 2 families from the Faroe Islands with GSD
III deficiency. The distribution supported the assumption of autosomal
recessive inheritance. Santer et al. (2001) reported 5 families from the
Faroe Islands affected with GSD IIIa. All carried the same mutation in
the AGL gene (R408X; 610860.0013) and were homozygous for the same
haplotype, supporting a founder effect. The results predicted a carrier
frequency of 1 in 30 and a calculated prevalence of 1 per 3,600 in the
Faroese population. The population of 45,000 of this small archipelago
in the North Atlantic has its roots in the colonization by Norwegians in
the 8th century and throughout the Viking Age. Santer et al. (2001)
concluded that due to a founder effect, the Faroe Islands have the
highest prevalence of GSD IIIa worldwide.

HISTORY

Fernandes (1995) stated that van Creveld (1928) published the first
clinical description of a patient with glycogen storage disease, a
7-year-old boy who presented with a markedly enlarged liver, obesity,
and small genitalia. The initial diagnosis of adiposogenital dystrophy
had to be abandoned because of the further clinical and metabolic
findings, the results of which were ingeniously interpreted as
reflecting increased combustion of fat resulting from 'insufficient
mobilization of glycogen.' This was the first reported patient with GSD
III, as proved later enzymatically. The description of GSD I by von
Gierke (1929) came next. Pompe (1932) described a case of 'idiopathic
hypertrophy of the heart,' now known to be GSD II. (Pompe was a close
friend of van Creveld and was killed by the Nazi Germans shortly before
the liberation of the Netherlands in 1944.)

ANIMAL MODEL

Ceh et al. (1976) described GSD III in the dog.

*FIELD* SA
Cohen and Friedman (1979); Confino et al. (1984); Garancis et al.
(1970); Miranda et al. (1981); Slonim et al. (1982); Waaler et al.
(1970)
*FIELD* RF
1. Aoyama, Y.; Ozer, I.; Demirkol, M.; Ebara, T.; Murase, T.; Podskarbi,
T.; Shin, Y. S.; Gokcay, G.; Okubo, M.: Molecular features of 23
patients with glycogen storage disease type III in Turkey: a novel
mutation p.R1147G associated with isolated glucosidase deficiency,
along with 9 AGL mutations. J. Hum. Genet. 54: 681-686, 2009.

2. Brunberg, J. A.; McCormick, W. F.; Schochet, S. S., Jr.: Type
III glycogenosis. An adult with diffuse weakness and muscle wasting. Arch.
Neurol. 25: 171-178, 1971.

3. Ceh, L.; Hauge, J. G.; Svenkerud, R.; Strande, A.: Glycogenosis
type III in the dog. Acta Vet. Scand. 17: 210-222, 1976.

4. Chen, Y.-T.; He, J.-K.; Ding, J.-H.; Brown, B. I.: Glycogen debranching
enzyme: purification, antibody characterization, and immunoblot analyses
of type III glycogen storage disease. Am. J. Hum. Genet. 41: 1002-1015,
1987.

5. Cleary, M. A.; Walter, J. H.; Kerr, B. A.; Wraith, J. E.: Facial
appearance in glycogen storage disease type III. Clin. Dysmorph. 11:
117-120, 2002.

6. Cohen, J.; Friedman, M.: Renal tubular acidosis associated with
type III glycogenosis. Acta Paediat. Scand. 68: 779-782, 1979.

7. Cohn, J.; Wang, P.; Hauge, M.; Henningsen, K.; Jensen, B.; Svejgaard,
A.: Amylo-1,6-glucosidase deficiency (glycogenosis type III) in the
Faroe Island. Hum. Hered. 25: 115-126, 1975.

8. Coleman, R. A.; Winter, H. S.; Wolf, B.; Chen, Y.-T.: Glycogen
debranching enzyme deficiency: long-term study of serum enzyme activities
and clinical features. J. Inherit. Metab. Dis. 15: 869-881, 1992.

9. Confino, E.; Pauzner, D.; Lidor, A.; Yedwab, G.; David, M.: Pregnancy
associated with amylo-1,6-glucosidase deficiency (Forbes' disease):
case report. Brit. J. Obstet. Gynaec. 91: 494-497, 1984.

10. DiMauro, S.; Hartwig, G. B.; Hays, A.; Eastwood, A. B.; Franco,
R.; Olarte, M.; Chang, M.; Roses, A. D.; Fetell, M.; Schoenfeldt,
R. S.; Stern, L. Z.: Debrancher deficiency: neuromuscular disorder
in 5 adults. Ann. Neurol. 5: 422-436, 1979.

11. Ding, J.-H.; de Barsy, T.; Brown, B. I.; Coleman, R. A.; Chen,
Y.-T.: Immunoblot analyses of glycogen debranching enzyme in different
subtypes of glycogen storage disease type III. J. Pediat. 116: 95-100,
1990.

12. Ebermann, I.; Elsayed, S. M.; Abdel-Ghaffar, T. Y.; Nurnberg,
G.; Nurnberg, P.; Elsobky, E.; Bolz, H. J.: Double homozygosity for
mutations of AGL and SCN9A mimicking neurohepatopathy syndrome. Neurology 70:
2343-2344, 2008.

13. Endo, Y.; Horinishi, A.; Vorgerd, M.; Aoyama, Y.; Ebara, T.; Murase,
T.; Odawara, M.; Podskarbi, T.; Shin, Y. S.; Okubo, M.: Molecular
analysis of the AGL gene: heterogeneity of mutations in patients with
glycogen storage disease type III from Germany, Canada, Afghanistan,
Iran, and Turkey. J. Hum. Genet. 51: 958-963, 2006.

14. Fellows, I. W.; Lowe, J. S.; Ogilvie, A.; Stevens, A.; Toghill,
P. J.; Atkinson, M.: Type III glycogenosis presenting as liver disease
in adults with atypical histological features. J. Clin. Path. 36:
431-434, 1983.

15. Fernandes, J.: The history of the glycogen storage disease. (Letter) Europ.
J. Pediat. 154: 423-424, 1995.

16. Garancis, J. C.; Panares, R. R.; Good, T. A.; Kuzma, J. F.: Type
3 glycogenosis. A biochemical and electron microscopic study. Lab.
Invest. 22: 468-477, 1970.

17. Hadjigeorgiou, G. M.; Comi, G. P.; Bordoni, A.; Shen, J.; Chen,
Y.-T.; Salani, S.; Toscano, A.; Fortunato, F.; Lucchiari, S.; Bresolin,
N.; Rodolico, C.; Piscaglia, M. G.; Franceschina, L.; Papadimitriou,
A.; Scarlato, G.: Novel donor splice site mutations of AGL gene in
glycogen storage disease type IIIa. J. Inherit. Metab. Dis. 22:
762-763, 1999.

18. Levin, S.; Moses, S. W.; Chayoth, R.; Jadoga, N.; Steinitz, K.
: Glycogen storage disease in Israel. A clinical, biochemical and
genetic study. Isr. J. Med. Sci. 3: 397-410, 1967.

19. Lucchiari, S.; Fogh, I.; Prelle, A.; Parini, R.; Bresolin, N.;
Melis, D.; Fiori, L.; Scarlato, G.; Comi, G. P.: Clinical and genetic
variability of glycogen storage disease type IIIa: seven novel AGL
gene mutations in the Mediterranean area. Am. J. Med. Genet. 109:
183-190, 2002.

20. Lucchiari, S.; Santoro, D.; Pagliarani, S.; Comi, G. P.: Clinical,
biochemical and genetic features of glycogen debranching enzyme deficiency. Acta
Myol. 26: 72-74, 2007.

21. Markowitz, A. J.; Chen, Y.-T.; Muenzer, J.; Delbuono, E. A.; Lucey,
M. R.: A man with type III glycogenosis associated with cirrhosis
and portal hypertension. Gastroenterology 105: 1882-1885, 1993.

22. Miranda, A. F.; DiMauro, S.; Antler, A.; Stern, L. Z.; Rowland,
L. P.: Glycogen debrancher deficiency is reproduced in muscle culture. Ann.
Neurol. 9: 283-288, 1981.

23. Momoi, T.; Sano, H.; Yamanaka, C.; Sasaki, H.; Mikawa, H.: Glycogen
storage disease type III with muscle involvement: reappraisal of phenotypic
variability and prognosis. Am. J. Med. Genet. 42: 696-699, 1992.

24. Moses, S. W.; Wanderman, K. L.; Myroz, A.; Frydman, M.: Cardiac
involvement in glycogen storage disease type III. Europ. J. Pediat. 148:
764-766, 1989.

25. Okubo, M.; Horinishi, A.; Takeuchi, M.; Suzuki, Y.; Sakura, N.;
Hasegawa, Y.; Igarashi, T.; Goto, K.; Tahara, H.; Uchimoto, S.; Omichi,
K.; Kanno, H.; Hayasaka, K.; Murase, T.: Heterogeneous mutations
in the glycogen-debranching enzyme gene are responsible for glycogen
storage disease type IIIa in Japan. Hum. Genet. 106: 108-115, 2000.

26. Parvari, R.; Moses, S.; Shen, J.; Hershkovitz, E.; Lerner, A.;
Chen, Y.-T.: A single-base deletion in the 3-prime coding region
of glycogen-debranching enzyme is prevalent in glycogen storage disease
type IIIA in a population of North African Jewish patients. Europ.
J. Hum. Genet. 5: 266-270, 1997.

27. Pompe, J. C.: Over Idiopathische hypertrophie van het hart. Nederl.
Tijdschr. Geneesk. 76: 304-312, 1932.

28. Rosenfeld, E. L.; Popova, I. A.; Chibisov, I. V.: Some cases
of type III glycogen storage disease. Clin. Chim. Acta 67: 123-130,
1976.

29. Santer, R.; Kinner, M.; Steuerwald, U.; Kjaergaard, S.; Skovby,
F.; Simonsen, H.; Shaiu, W.-L.; Chen, Y.-T.; Schneppenheim, R.; Schaub,
J.: Molecular genetic basis and prevalence of glycogen storage disease
type IIIA in the Faroe Islands. Europ. J. Hum. Genet. 9: 388-391,
2001.

30. Schoser, B.; Glaser, D.; Muller-Hocker, J.: Clinicopathological
analysis of the homozygous p.W1327X AGL mutation in glycogen storage
disease type 3. Am. J. Med. Genet. 146A: 2911-2915, 2008.

31. Shaiu, W.-L.; Kishnani, P. S.; Shen, J.; Liu, H.-M.; Chen, Y.-T.
: Genotype-phenotype correlation in two frequent mutations and mutation
update in type III glycogen storage disease. Molec. Genet. Metab. 69:
16-23, 2000.

32. Shen, J,; Bao, Y.; Chen, Y.-T.: A nonsense mutation due to a
single base insertion in the 3-prime-coding region of glycogen debranching
enzyme gene associated with a severe phenotype in a patient with glycogen
storage disease type IIIa. Hum. Mutat. 9: 37-40, 1997.

33. Shen, J.; Bao, Y.; Liu, H.-M.; Lee, P.; Leonard, J. V.; Chen,
Y.-T.: Mutations in exon 3 of the glycogen debranching enzyme gene
are associated with glycogen storage disease type III that is differentially
expressed in liver and muscle. J. Clin. Invest. 98: 352-357, 1996.

34. Shen, J.; Liu, H.-M.; Bao, Y.; Chen, Y.-T.: Polymorphic markers
of the glycogen debranching enzyme gene allowing linkage analysis
in families with glycogen storage disease type III. J. Med. Genet. 34:
34-38, 1997.

35. Slonim, A. E.; Weisberg, C.; Benke, P.; Evans, O. B.; Burr, I.
M.: Reversal of debrancher deficiency myopathy by the use of high-protein
nutrition. Ann. Neurol. 11: 420-422, 1982.

36. Talente, G. M.; Coleman, R. A.; Alter, C.; Baker, L.; Brown, B.
I.; Cannon, R. A.; Chen, Y.-T.; Crigler, J. F., Jr.; Ferreira, P.;
Haworth, J. C.; Herman, G. E.; Issenman, R. M.; Keating, J. P.; Linde,
R.; Roe, T. F.; Senior, B.; Wolfsdorf, J. I.: Glycogen storage disease
in adults. Ann. Intern. Med. 120: 218-226, 1994.

37. van Creveld, S.: Over een bijzondere stoornis in de koolhydraatstof-Wisseling
in den kinderleeftijd. Nederl. Maandschr. Geneesk 8: 349-359, 1928.

38. Van Hoof, F.; Hers, H. G.: The subgroups of type III glycogenosis. Europ.
J. Biochem. 2: 265-270, 1967.

39. von Gierke, E.: Hepato-nephromegalia glykogenica (Glykogenspeicherkrankheit
der Leber und Nieren.). Beitr. Path. Anat. 82: 497-513, 1929.

40. Waaler, P. E.; Garatun-Tjeldsto, O.; Moe, P. J.: Genetic studies
in glycogen storage disease type III. Acta Paediat. Scand. 59: 529-535,
1970.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Height];
Short stature;
[Other];
Growth retardation

HEAD AND NECK:
[Face];
Midface hypoplasia;
[Eyes];
Deep-set eyes;
[Nose];
Depressed nasal bridge;
Broad upturned nasal tip;
[Mouth];
Bow-shaped lips;
Thin vermilion border

CARDIOVASCULAR:
[Heart];
Cardiomyopathy;
Ventricular hypertrophy on ECG

ABDOMEN:
[Liver];
Hepatomegaly;
Hepatic fibrosis

MUSCLE, SOFT TISSUE:
Muscle weakness (increases with age);
Distal muscle wasting;
Myopathy;
Muscle biopsy shows vacuoles containing PAS-positive glycogen

METABOLIC FEATURES:
Hypoglycemia

LABORATORY ABNORMALITIES:
Amylo-1,6-glucosidase deficiency;
Hypoglycemia;
Hyperlipidemia;
Normal blood lactate;
Normal uric acid;
Elevated transaminases;
Increased serum creatine kinase

MISCELLANEOUS:
Type IIIa has both liver and muscle involvement;
Type IIIb liver involvement only (15% of all cases);
Liver symptoms improve with age and disappear after puberty;
Muscle weakness increases with age

MOLECULAR BASIS:
Caused by mutation in the amylo-1,6-glucosidase, 4-alpha-glucanotransferase
gene (AGL, 610860.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 3/26/2007
Kelly A. Przylepa - updated: 10/5/2004
Kelly A. Przylepa - revised: 9/20/2000

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 07/02/2013
joanna: 12/2/2011
ckniffin: 3/2/2009
ckniffin: 3/26/2007
ckniffin: 10/6/2004
joanna: 10/5/2004
joanna: 3/19/2002
joanna: 3/18/2002
kayiaros: 9/20/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 12/20/2010
Cassandra L. Kniffin - updated: 6/10/2010
Cassandra L. Kniffin - updated: 3/3/2009
Cassandra L. Kniffin - updated: 2/7/2008
Cassandra L. Kniffin - reorganized: 3/22/2007
Cassandra L. Kniffin - updated: 3/21/2007
Siobhan M. Dolan - updated: 7/2/2004
Victor A. McKusick - updated: 5/21/2002
Michael B. Petersen - updated: 11/6/2001
Victor A. McKusick - updated: 8/17/2000
Ada Hamosh - updated: 6/9/2000
Victor A. McKusick - updated: 2/17/2000
Victor A. McKusick - updated: 12/21/1999
Jennifer P. Macke - updated: 12/3/1999
Victor A. McKusick - updated: 10/7/1999
Ada Hamosh - updated: 6/17/1998
Victor A. McKusick - updated: 12/19/1997
Jennifer P. Macke - updated: 7/15/1997
Victor A. McKusick - updated: 3/28/1997

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
terry: 03/20/2012
terry: 10/11/2011
terry: 4/21/2011
carol: 2/15/2011
ckniffin: 12/20/2010
terry: 10/12/2010
wwang: 6/11/2010
ckniffin: 6/10/2010
wwang: 3/10/2009
ckniffin: 3/3/2009
carol: 2/3/2009
terry: 6/6/2008
wwang: 2/21/2008
ckniffin: 2/7/2008
wwang: 11/20/2007
terry: 5/9/2007
carol: 4/17/2007
carol: 3/22/2007
ckniffin: 3/21/2007
terry: 11/15/2006
ckniffin: 1/5/2006
carol: 8/1/2005
carol: 7/6/2004
terry: 7/2/2004
alopez: 3/17/2004
cwells: 6/4/2002
cwells: 6/3/2002
terry: 5/21/2002
cwells: 11/9/2001
cwells: 11/6/2001
mcapotos: 8/30/2000
mcapotos: 8/29/2000
terry: 8/17/2000
alopez: 6/16/2000
terry: 6/9/2000
alopez: 2/29/2000
terry: 2/17/2000
carol: 1/28/2000
mcapotos: 1/19/2000
mcapotos: 1/11/2000
mcapotos: 1/7/2000
terry: 12/21/1999
alopez: 12/3/1999
terry: 11/24/1999
carol: 10/7/1999
carol: 9/22/1999
carol: 3/17/1999
alopez: 6/17/1998
dholmes: 6/16/1998
mark: 1/10/1998
terry: 12/19/1997
jenny: 9/2/1997
jenny: 8/14/1997
jenny: 3/31/1997
terry: 3/31/1997
terry: 3/28/1997
terry: 3/20/1997
mark: 1/30/1997
terry: 1/24/1997
terry: 1/22/1997
mark: 9/6/1996
terry: 8/29/1996
terry: 3/26/1996
mark: 10/5/1995
carol: 1/18/1995
davew: 6/2/1994
mimadm: 4/13/1994
carol: 2/10/1993
carol: 11/18/1992

MIM 610860
*RECORD*
*FIELD* NO
610860
*FIELD* TI
*610860 AMYLO-1,6-GLUCOSIDASE, 4-ALPHA-GLUCANOTRANSFERASE; AGL
;;GLYCOGEN DEBRANCHER ENZYME; GDE
read more*FIELD* TX

DESCRIPTION

The AGL gene encodes the glycogen debrancher enzyme, a large monomeric
protein with a molecular mass of approximately 160 kD. The enzyme has 2
catalytic activities: amylo-1,6-glucosidase (EC 3.2.1.33) and
4-alpha-glucanotransferase (EC 2.4.1.25). The 2 activities are
determined at separate catalytic sites on the polypeptide chain and can
function independently of each other. Both activities and glycogen
binding are required for complete function (Shen et al., 1996; Endo et
al., 2006).

CLONING

Yang et al. (1992, 1992) isolated a full-length cDNA corresponding to
the human muscle glycogen debranching enzyme. The deduced 1,532-residue
protein has a molecular mass of approximately 173 kD. Northern blot
analysis detected a 7-kb mRNA transcript. The liver mRNA sequence is
identical to the muscle sequence for most of the length, except for the
5-prime end in which the liver sequence diverges completely from the
muscle sequence, beginning with the putative transcription initiation
site to the ninth nucleotide upstream of the translation initiation
codon. Thus, the muscle and liver isoforms are generated via
differential RNA transcription, with an alternative first exon usage,
from a single gene. Shen et al. (1997) cited their unpublished data
indicating that 17 additional amino acids precede the N terminus of the
AGL gene sequence published by Yang et al. (1992).

Bao et al. (1996) stated that there are at least 6 isoforms of AGL
produced by alternative splicing. The major isoform, isoform 1, begins
transcription at exon 1 and begins translation at exon 3.
Muscle-specific isoforms (2, 3, and 4) begin transcription at exon 2.
Minor isoforms (5 and 6) begin further within the gene. Reporter assays
revealed that promoter region 1 (for isoform 1) was functional in liver,
muscle, and ovary, while promoter region 2 (for isoforms 2, 3, and 4)
was active only in muscle cells. The authors concluded that the human
AGL gene contains at least 2 promoter regions that confer differential
expression of isoform mRNAs in a tissue-specific manner.

GENE FUNCTION

Cheng et al. (2007) showed that malin (NHLRC1; 608072), an E3 ubiquitin
ligase mutated in Lafora disease (254780), interacted with mouse Agl and
promoted its ubiquitination. Transfection studies in HepG2 cells showed
that Agl was cytoplasmic, whereas malin was predominantly nuclear.
However, after depletion of glycogen stores, about 90% of transfected
cells exhibited partial nuclear Agl staining. Elevation of cAMP
increased malin levels and malin/Agl complex formation. Refeeding mice
for 2 hours after overnight fasting reduced hepatic Agl levels by 48%.
Cheng et al. (2007) concluded that binding of glycogen regulates the
stability of AGL and that ubiquitination of AGL may play a role in the
pathophysiology of both Lafora disease and Cori disease (232400).

GENE STRUCTURE

Bao et al. (1996) determined that the AGL gene is encoded by 35 exons
spanning 85 kb of genomic DNA.

MAPPING

Yang-Feng et al. (1992) mapped the AGL gene to chromosome 1p21 by
somatic cell hybrid analysis and in situ hybridization.

MOLECULAR GENETICS

In 3 unrelated patients with glycogen storage disease IIIb (GSD3;
232400), Shen et al. (1996) identified homozygous or compound
heterozygous mutations in the AGL gene (see, e.g.,
610860.0002-610860.0004). One of the mutations (17delAG; 610860.0004)
was found in 8 of 10 additional GSD IIIb patients. Mutations in exon 3
were present in 12 of 13 GSD IIIb patients, suggesting a specific
association.

Shen et al. (1997) identified a homozygous mutation in the AGL gene
(610860.0001) in a child with an unusually severe GSD IIIa phenotype.

Okubo et al. (1998) identified a homozygous mutation in the AGL gene
(610860.0006) in a Japanese patient with GSD IIIb.

Hadjigeorgiou et al. (1999) reported 4 adult Italian patients with GSD
IIIa. All of the patients had a history of infantile hepatomegaly
followed by myopathy in their twenties. AGL activity and protein were
almost absent in muscle specimens. RT-PCR revealed truncated muscle AGL
cDNA in all 4 patients due to skipping of different exons. Hadjigeorgiou
et al. (1999) commented that the AGL gene mutations described to date
account for less than half of the total mutant alleles.

In Japan, Okubo et al. (2000) investigated 8 Japanese GSD IIIa patients
from 7 families and identified 7 mutations, including 1 splicing
mutation (610860.0007) that they had previously reported (Okubo et al.,
1996), together with 6 novel ones.

Shaiu et al. (2000) reported 2 frequent mutations, each of which was
found in the homozygous state in multiple patients, and each of which
was associated with a subset of clinical phenotype in those patients
with that mutation. One mutation, IVS32-12A-G (610860.0006), was
identified in homozygosity in a confirmed GSD IIIa Caucasian patient who
presented with mild clinical symptoms. This mutation had an allele
frequency of approximately 5.5% in GSD III patients tested. The other
common mutation, 3964delT (610860.0010), was identified in an African
American patient who had a severe phenotype and early onset of clinical
symptoms. The mutation was later identified in several other patients
and was observed at a frequency of approximately 6.7%. Together, these 2
mutations can account for more than 12% of the molecular defects in GSD
III patients. Shaiu et al. (2000) also identified 6 additional mutations
and reviewed the nonmutation state.

Lucchiari et al. (2002) identified 7 novel mutations of the AGL gene in
patients with GSD IIIa in the Mediterranean area.

Endo et al. (2006) identified 9 different mutations in the AGL gene,
including 6 novel mutations, among 9 patients with GSD III. The patients
were from Germany, Canada, Afghanistan, Iran, and Turkey.

Aoyama et al. (2009) identified 10 different AGL mutations, including 8
novel mutations (see, e.g., 610860.0014 and 610860.0015), in 23 Turkish
patients with GSD III. No genotype/phenotype correlations were observed.

PATHOGENESIS

Cheng et al. (2009) studied 4 rare AGL mutations, including G1448R
(610860.0009), to determine the molecular basis of GSD III pathogenesis.
The L620P mutation primarily abolished transferase activity in
transfected cells, while the R1147G (610860.0014) mutation only impaired
glucosidase function. The R1448R and Y1445ins mutations in the
carbohydrate-binding domain (CBD) were more severe in nature, leading to
significant loss of all enzymatic activities and carbohydrate binding
ability, as well as enhancing targeting for proteasomal degradation.
Cheng et al. (2009) concluded that inactivation of either enzymatic
activity is sufficient to cause GSD III disease, and suggested that the
CBD of AGL may play a major role to coordinate its functions and
regulation by the ubiquitin-proteasome system.

*FIELD* AV
.0001
GLYCOGEN STORAGE DISEASE, TYPE IIIa
AGL, 1-BP INS, 4529A

In a child with an unusually severe phenotype of glycogen storage
disease type IIIa (232400) manifested in both liver and muscle, Shen et
al. (1997) identified a homozygous 1-bp insertion (4529insA) in the
3-prime coding region of the AGL gene. The mutation created a
termination codon at residue 1510 of their sequence. (They stated that
amino acid residue 1510 in their study corresponded to residue 1493 of
the Yang et al. (1992) sequence.) The child had recurrent hypoglycemia,
seizures, severe cardiomegaly, and hepatomegaly, and died at 4 years of
age.

.0002
GLYCOGEN STORAGE DISEASE, TYPE IIIb
AGL, GLN6TER

In a 41-year-old patient with hepatic glycogen storage disease type III
(232400), but with no clinical or laboratory evidence of myopathy or
cardiomyopathy, Shen et al. (1996) demonstrated compound heterozygosity
for 2 mutations in the AGL gene: a 16C-T transition, resulting in a
gln6-to-ter (Q6X) substitution and W680X (610860.0003).

.0003
GLYCOGEN STORAGE DISEASE, TYPE IIIb
AGL, TRP680TER

In a 41-year-old patient with hepatic glycogen storage disease type III
(232400), but with no clinical or laboratory evidence of myopathy or
cardiomyopathy, Shen et al. (1996) demonstrated compound heterozygosity
for 2 mutations in the AGL gene: a 2039G-A transition, resulting in a
trp680-to-ter (W680X) substitution, and Q6X (610860.0002).

.0004
GLYCOGEN STORAGE DISEASE, TYPE IIIb
AGL, 2-BP DEL, 17AG

In 10 of 13 patients with GSD IIIb (232400), Shen et al. (1996)
identified a 2-bp deletion (17delAG) in the AGL gene, resulting in a
truncated protein.

.0005
GLYCOGEN STORAGE DISEASE, TYPE IIIa
AGL, 1-BP DEL, 4455T

In 13 patients with GSD III (232400) from 11 families, Parvari et al.
(1997) identified a homozygous 1-bp deletion (4455delT) in exon 34 of
the AGL gene, resulting in a frameshift and truncation of the last 30
amino acid residues of the protein. All patients were of North African
Jewish descent and had liver and muscle involvement. While all patients
showed the characteristic features related to the liver enzyme
deficiency, the peripheral muscular impairment varied from minimal to
severe, with neuromuscular involvement. The mutation appeared to be
ethnic-specific as it was not seen in 18 patients of different ethnic
origins.

.0006
GLYCOGEN STORAGE DISEASE, TYPE IIIb
GLYCOGEN STORAGE DISEASE, TYPE IIIa, INCLUDED
AGL, IVS32AS, A-G, -12

In a 31-year-old Japanese female with GSD type IIIb (232400), Okubo et
al. (1998) detected a homozygous A-to-G transition in the AGL gene 12 bp
upstream of exon 33 that caused activation of a cryptic splice site and
insertion of an extra 11 bp of intronic sequence between exons 32 and
33. The mutation was predicted to change the last 15 consecutive
C-terminal amino acids before premature termination at codon 1436 and
loss of 112 terminal amino acids. The patient's parents were first
cousins.

Shaiu et al. (2000) identified this mutation in homozygosity in a GSD
type IIIa Caucasian patient presenting with mild clinical symptoms. They
found that the IVS32-12A-G mutation had an allelic frequency of about
5.5% in the GSD III patients tested.

.0007
GLYCOGEN STORAGE DISEASE, TYPE IIIa
AGL, IVS14DS, G-T, +1

In a Japanese man with glycogen storage disease type IIIa (232400),
Okubo et al. (1996) reported heterozygosity for a 124-bp deletion in the
AGL gene, corresponding to a single exon. The deletion resulted from a
G-to-T transversion at the donor splice site immediately downstream of
the deletion. The mutation was predicted to result in a truncated
enzyme. This was the first mutation in the AGL gene identified in a
patient with GSD III. The patient was a 43-year-old Japanese man who had
been diagnosed with GSD III at 18 years of age. He had hepatomegaly and
muscle weakness. Family history showed no consanguinity. The patient's
asymptomatic father and son were also heterozygous for the mutation.
Southern blot analysis of the patient's genomic DNA showed an
additional, unique EcoRI fragment of 5.8 kb, inherited from the mother
(610860.0008).

.0008
GLYCOGEN STORAGE DISEASE, TYPE IIIa
AGL, EcoRI FRAGMENT INS

See 610860.0007 and Okubo et al. (1996).

.0009
GLYCOGEN STORAGE DISEASE, TYPE IIIa
AGL, GLY1448ARG

In a Japanese patient, born from a consanguineous family, with GSD IIIa
(232400), Okubo et al. (1999) identified a homozygous 4742G-C
transversion in exon 33 of the AGL gene, resulting in a gly1448-to-arg
(G1448R) substitution in a putative glycogen-binding site that is
indispensable for enzyme activity. The authors claimed that this was the
first report of a missense mutation associated with GSD III.

Cheng et al. (2007) showed that mouse Agl with the G1448R mutation was
unable to bind glycogen and displayed decreased stability that was
rescued by proteasome inhibition. Agl G1148R was more highly
ubiquitinated than wildtype Agl.

.0010
GLYCOGEN STORAGE DISEASE, TYPE IIIa
AGL, 1-BP DEL, 3964T

In a 25-year-old African American female with GSD IIIa (232400), Shaiu
et al. (2000) identified a homozygous 1-bp deletion (3964delT) in the
AGL gene. She presented with hepatomegaly, symptomatic hypoglycemia, and
failure to thrive at 1 year of age. Muscle involvement as truncal
hypotonia and proximal upper and lower extremity weakness were noted
since 7 years of age, with CPK values ranging from 300 to 1,000 IU. At
25 years of age, progressive myopathy, hepatomegaly, and repeated
episodes of hypoglycemia were apparent. This mutation was subsequently
identified in homozygosity in several patients with similar presentation
and had an overall frequency of around 6.7% in the GSD III patients
tested.

.0011
GLYCOGEN STORAGE DISEASE, TYPE IIIb
AGL, 1-BP DEL, 2399C

In a 2-year-old GSD IIIa (232400) patient of mixed Asian ancestry, Okubo
et al. (2000) observed compound heterozygosity for 2 mutations in the
AGL gene: a deletion of 2399C in exon 16 inherited from the Japanese
father, and a G-to-A transition at position +5 at the donor splice site
of intron 33 (610860.0012) inherited from the Chinese mother. The girl
had been admitted to hospital because of liver dysfunction. Hepatomegaly
was first noted at age 4 months. She had experienced occasional
hypoglycemia, and growth retardation was noted. Muscular manifestations
were not described.

.0012
GLYCOGEN STORAGE DISEASE, TYPE IIIb
AGL, IVS33DS, G-A, +5

See Okubo et al. (2000) and (610860.0011).

.0013
GLYCOGEN STORAGE DISEASE, TYPE IIIa
AGL, ARG408TER

In 6 children from 5 families with GSD IIIa (232400) from the Faroe
Islands, Santer et al. (2001) identified a homozygous 1222C-T transition
in the AGL gene, resulting in an arg408-to-ter substitution (R408X). All
patients were homozygous for the same haplotype defined by 5 intragenic
polymorphisms, supporting a founder effect. The R408X mutation was also
detected in compound heterozygosity in 2 of 50 GSD IIIa patients of
other European or North American origin. Whereas the mutation was not
detected in 198 German newborns, 9 of 272 Faroese newborns were
heterozygous, predicting a carrier frequency of 1 in 30 and a calculated
prevalence of 1 per 3,600 in the Faroese population. The population of
45,000 of this small archipelago in the North Atlantic has its roots in
the colonization by Norwegians in the 8th century and throughout the
Viking Age. Santer et al. (2001) concluded that due to a founder effect,
the Faroe Islands have the highest prevalence of GSD IIIa worldwide.

.0014
GLYCOGEN STORAGE DISEASE, TYPE IIIc
AGL, ARG1147GLY

In a 14-year-old Turkish girl with isolated glucosidase deficiency,
known as glycogen storage disease type IIIc (232400), Aoyama et al.
(2009) identified a homozygous 3439A-G transition in exon 27 of the AGL
gene, resulting in an arg1147-to-gly (R1147G) substitution in a
conserved residue in the C-terminal region. The patient had mild
hepatomegaly, but did not have hypoglycemia or clinical muscle
involvement. Cheng et al., 2009 showed that the R1147G-mutant protein
lost glucosidase activity, but retained 40% of transferase activity
compared to wildtype.

.0015
GLYCOGEN STORAGE DISEASE, TYPE IIIa
AGL, TRP1327TER

In 6 Turkish patients with glycogen storage disease type IIIa (232400),
Aoyama et al. (2009) identified a homozygous 3980G-A transition in exon
31 of the AGL gene, resulting in a trp1327-to-ter (W1327X) substitution.
All 6 patients were from 2 cities in the eastern Black Sea region, and
haplotype analysis indicated a founder effect.

*FIELD* SA
Talente et al. (1994)
*FIELD* RF
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*FIELD* CN
Cassandra L. Kniffin - updated: 6/10/2010
George E. Tiller - updated: 2/24/2010
Patricia A. Hartz - updated: 11/2/2007

*FIELD* CD
Cassandra L. Kniffin: 3/19/2007

*FIELD* ED
wwang: 06/11/2010
ckniffin: 6/10/2010
wwang: 2/26/2010
terry: 2/24/2010
mgross: 11/2/2007
terry: 11/2/2007
carol: 3/22/2007
ckniffin: 3/21/2007