GYS2

Summary

GYS2 (glycogen synthase 2, HGNC:4707) is a protein-coding gene on chromosome 12p12.1, encoding Glycogen [starch] synthase, liver (P54840). Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme.

The protein encoded by this gene, liver glycogen synthase, catalyzes the rate-limiting step in the synthesis of glycogen - the transfer of a glucose molecule from UDP-glucose to a terminal branch of the glycogen molecule. Mutations in this gene cause glycogen storage disease type 0 (GSD-0) - a rare type of early childhood fasting hypoglycemia with decreased liver glycogen content.

Source: NCBI Gene 2998 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycogen storage disorder due to hepatic glycogen synthase deficiency (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 374 total — 18 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 18
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_021957

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4707
Approved symbol	GYS2
Name	glycogen synthase 2
Location	12p12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111713
Ensembl biotype	protein_coding
OMIM	138571
Entrez	2998

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000261195, ENST00000863010, ENST00000863011, ENST00000863012, ENST00000863013, ENST00000863014, ENST00000863015

RefSeq mRNA: 1 — MANE Select: NM_021957 NM_021957

CCDS: CCDS8690

Canonical transcript exons

ENST00000261195 — 16 exons

Exon	Start	End
ENSE00000726100	21539258	21539338
ENSE00000726105	21540410	21540573
ENSE00000726109	21542496	21542591
ENSE00000726114	21546344	21546470
ENSE00000726121	21558200	21558313
ENSE00000726126	21559091	21559169
ENSE00000726130	21559651	21559710
ENSE00000726140	21560386	21560492
ENSE00000726146	21562918	21563038
ENSE00000726152	21563228	21563345
ENSE00000726159	21568865	21569009
ENSE00000726165	21574144	21574326
ENSE00000726170	21575866	21576057
ENSE00000726175	21580342	21580523
ENSE00000822269	21604472	21604847
ENSE00001142024	21536107	21537175

Expression profiles

Bgee: expression breadth broad, 51 present calls, max score 94.02.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3083 / max 113.0559, expressed in 16 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130028	0.1660	14
130027	0.1020	13
130029	0.0404	11

Top tissues by expression

105 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	94.02	gold quality
liver	UBERON:0002107	93.24	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.77	gold quality
lower esophagus mucosa	UBERON:0035834	78.35	gold quality
esophagus mucosa	UBERON:0002469	66.24	gold quality
subcutaneous adipose tissue	UBERON:0002190	61.90	gold quality
vagina	UBERON:0000996	55.84	gold quality
adipose tissue	UBERON:0001013	50.47	gold quality
esophagus	UBERON:0001043	48.82	gold quality
body of pancreas	UBERON:0001150	46.05	gold quality
colonic epithelium	UBERON:0000397	41.33	gold quality
pancreas	UBERON:0001264	40.17	gold quality
right coronary artery	UBERON:0001625	39.11	silver quality
thoracic mammary gland	UBERON:0005200	39.08	gold quality
bone marrow cell	CL:0002092	38.05	gold quality
adult mammalian kidney	UBERON:0000082	37.67	silver quality
ectocervix	UBERON:0012249	37.58	gold quality
kidney	UBERON:0002113	37.19	silver quality
metanephros cortex	UBERON:0010533	36.69	silver quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
omental fat pad	UBERON:0010414	35.87	gold quality
saliva-secreting gland	UBERON:0001044	35.67	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
minor salivary gland	UBERON:0001830	35.45	gold quality
skeletal muscle tissue	UBERON:0001134	34.94	gold quality
uterine cervix	UBERON:0000002	33.91	gold quality
gall bladder	UBERON:0002110	33.79	silver quality
bone marrow	UBERON:0002371	32.71	gold quality
right hemisphere of cerebellum	UBERON:0014890	32.65	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CLOCK, PPARA, PPARD, PPARG

miRNA regulators (miRDB)

58 targeting GYS2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-4261	99.59	70.30	3415

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 7)

• The GYS2 gene is a new susceptibility gene that significantly affects the risk for ovary syndrome through obesity-related conditions. (PMID:22951595)
• Sequencing of the GYS2 gene is more likely to be positive in patients with fasting ketotic hypoglycaemia and concomitant postprandial hyperglycaemia with hyperlactataemia. (PMID:23426827)
• Mutation in GYS2 gene is associated with hepatic glycogen synthase deficiency. (PMID:28245189)
• Findings suggest that GYS2 serves as a prognostic factor and functions as a tumor suppressor in HCC. The newly identified HBx/GYS2/p53 axis is responsible for the deregulation of glycogen metabolism. (PMID:30584071)
• A patient with glycogen storage disease type 0 and a novel sequence variant in GYS2: a case report and literature review. (PMID:32779500)
• Value of glycogen synthase 2 in intrahepatic cholangiocarcinoma prognosis assessment and its influence on the activity of cancer cells. (PMID:34783271)
• Whole-Exome sequencing identifies GYS2 biallelic variants in individuals with suspected epilepsy. (PMID:37574425)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gys2	ENSDARG00000004904
mus_musculus	Gys2	ENSMUSG00000030244
rattus_norvegicus	Gys2	ENSRNOG00000059753
drosophila_melanogaster	Glys	FBGN0266064
caenorhabditis_elegans		WBGENE00001793

Paralogs (1): GYS1 (ENSG00000104812)

Protein

Protein identifiers

Glycogen [starch] synthase, liver — P54840 (reviewed: P54840)

Alternative names: Glycogen synthase 2

All UniProt accessions (1): P54840

UniProt curated annotations — full annotation on UniProt →

Function. Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme. Extends the primer composed of a few glucose units formed by glycogenin by adding new glucose units to it. In this context, glycogen synthase transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan.

Subunit / interactions. Part of the glycogen synthase (GS)-glycogenin complex, a heterooctamer composed of a tetramer of GS and 2 dimers of glycogenin, where each GS protomer binds to one glycogenin subunit (via glycogenin C-terminus); the GS tetramer may dissociate from glycogenin dimers to continue glycogen polymerization on its own. May also form a heterooctamer complex with GYG1 (via GYG1 C-terminus).

Tissue specificity. Specifically expressed in liver (at protein level).

Post-translational modifications. Primed phosphorylation at Ser-657 (site 5) by CSNK2A1 and CSNK2A2 is required for inhibitory phosphorylation at Ser-641 (site 3a), Ser-645 (site 3b), Ser-649 (site 3c) and Ser-653 (site 4) by GSK3A an GSK3B. Dephosphorylation at Ser-641 and Ser-645 by PP1 activates the enzyme. Phosphorylation at Ser-8 is not required for interaction with GYG1. Interaction with GYG1 does not regulate the phosphorylation at Ser-8 and Ser-641.

Disease relevance. Glycogen storage disease 0 (GSD0) [MIM:240600] A metabolic disorder characterized by fasting hypoglycemia presenting in infancy or early childhood, high blood ketones and low alanine and lactate concentrations. Although feeding relieves symptoms, it often results in postprandial hyperglycemia and hyperlactatemia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Allosteric activation by glucose-6-phosphate. Phosphorylation reduces the activity towards UDP-glucose. When in the non-phosphorylated state, glycogen synthase does not require glucose-6-phosphate as an allosteric activator; when phosphorylated it does.

Pathway. Glycan biosynthesis; glycogen biosynthesis.

Similarity. Belongs to the glycosyltransferase 3 family.

RefSeq proteins (1): NP_068776* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008631	Glycogen_synth	Family

Pfam: PF05693

Catalyzed reactions (Rhea), 1 shown:

• (1->4)-alpha-D-glucosyl + UDP-alpha-D-glucose = (1->4)-alpha-D-glucosyl + UDP + H(+) (RHEA:18549)

UniProt features (47 total): binding site 17, modified residue 9, sequence variant 9, sequence conflict 8, compositionally biased region 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54840-F1	87.08	0.76

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (17): 297; 301; 331; 331; 501; 510; 512; 513; 515; 582; 586; 40 …

Post-translational modifications (9): 8, 11, 627, 641, 645, 649, 653, 657, 683

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3322077	Glycogen synthesis
R-HSA-3858516	Glycogen storage disease type 0 (liver GYS2)
R-HSA-3878781	Glycogen storage disease type IV (GBE1)

MSigDB gene sets: 0 (showing top):

GO Biological Process (2): glycogen biosynthetic process (GO:0005978), response to glucose (GO:0009749)

GO Molecular Function (5): alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity (GO:0004373), glycogen synthase activity, transferring glucose-1-phosphate (GO:0061547), catalytic activity (GO:0003824), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (5): cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), cell cortex (GO:0005938), cortical actin cytoskeleton (GO:0030864)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Glycogen storage diseases	2
Glycogen metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cytoplasm	2
glycogen metabolic process	1
glucan biosynthetic process	1
response to hexose	1
alpha-1,4-glucan glucosyltransferase (NDP-glucose donor) activity	1
UDP-glucosyltransferase activity	1
transferase activity, transferring phosphorus-containing groups	1
molecular_function	1
catalytic activity	1
transferase activity	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
cell periphery	1
actin cytoskeleton	1
cortical cytoskeleton	1

Protein interactions and networks

STRING

2279 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GYS2	PYGL	P06737	960
GYS2	PYGB	P11216	908
GYS2	PYGM	P11217	856
GYS2	GBE1	Q04446	743
GYS2	PPP1R3B	Q86XI6	700
GYS2	AGL	P35573	692
GYS2	GYG1	P46976	677
GYS2	G6PC1	P35575	667
GYS2	INS	P01308	663
GYS2	GYG2	O15488	654
GYS2	UGP2	Q16851	646
GYS2	SLC37A4	O43826	642
GYS2	PCK1	P35558	624
GYS2	PPP1CA	P08129	617
GYS2	GCK	P35557	570

IntAct

9 interactions, top by confidence:

A	B	Type	Score
PPP1CA	CCDC85C	psi-mi:“MI:0914”(association)	0.670
GYG2	GYS1	psi-mi:“MI:0914”(association)	0.660
GYS2	GYG2	psi-mi:“MI:0915”(physical association)	0.550
STBD1	MID1	psi-mi:“MI:0914”(association)	0.530
PPP1R3C	STBD1	psi-mi:“MI:0914”(association)	0.530
GYS2	TNFRSF1A	psi-mi:“MI:0915”(physical association)	0.370
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
GABARAP		psi-mi:“MI:0914”(association)	0.350

BioGRID (19): GYS2 (Affinity Capture-MS), GYS2 (Affinity Capture-MS), GYS2 (Affinity Capture-MS), GYS2 (Affinity Capture-MS), GYS2 (Affinity Capture-MS), GYS2 (Affinity Capture-MS), GYS2 (Affinity Capture-MS), TP53 (Affinity Capture-Western), GYS2 (Affinity Capture-Western), TP53 (Reconstituted Complex), MDM2 (Affinity Capture-Western), GYS2 (Affinity Capture-Western), MDM2 (Reconstituted Complex), GYS2 (Affinity Capture-MS), GYS2 (Affinity Capture-MS)

ESM2 similar proteins: A1A5G6, A7Z064, G5EEK9, G5EGP4, O13742, O97681, P00347, P00365, P04035, P09610, P10759, P13807, P15920, P16393, P17625, P20715, P23109, P25286, P30628, P32563, P37296, P38329, P54840, P57103, P70549, Q00955, Q01237, Q01290, Q01432, Q09573, Q1W675, Q29466, Q29512, Q54E04, Q5R422, Q5R6N3, Q5R9H0, Q8AVM5, Q8MJ26, Q8RWZ7

Diamond homologs: A2RRU1, A7MB78, J9VTK7, O93869, P13807, P13834, P17625, P23337, P27472, P54840, Q55GH4, Q5R9H0, Q8MJ26, Q8VCB3, Q9U2D9, Q9VFC8, Q9Z1E4

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
GYS2	“down-regulates quantity”	UDP-alpha-D-glucose(2-)	“chemical modification”
GYS2	“up-regulates quantity”	α-D-glucosyl-glycogenin	“chemical modification”
PPP1R3C	up-regulates	GYS2	binding
PPP1R3B	up-regulates	GYS2	binding
AMPK	“down-regulates activity”	GYS2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

374 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	20
Uncertain significance	148
Likely benign	87
Benign	54

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323047	NM_021957.4(GYS2):c.1094_1098del (p.Phe365fs)	Pathogenic
16050	NM_021957.4(GYS2):c.941+1G>C	Pathogenic
16055	NM_021957.4(GYS2):c.1447T>C (p.Ser483Pro)	Pathogenic
1806174	NM_021957.4(GYS2):c.522T>G (p.Tyr174Ter)	Pathogenic
2093847	NM_021957.4(GYS2):c.376_377del (p.Asn126fs)	Pathogenic
214529	NM_021957.4(GYS2):c.547C>T (p.Gln183Ter)	Pathogenic
214537	NM_021957.4(GYS2):c.942-42_974del	Pathogenic
3244318	NC_000012.11:g.(?21733256)(21757526_?)del	Pathogenic
3244319	NC_000012.11:g.(?21689888)(21711267_?)del	Pathogenic
3339273	NM_021957.4(GYS2):c.50dup (p.Trp18fs)	Pathogenic
3768522	NM_021957.4(GYS2):c.13C>T (p.Arg5Ter)	Pathogenic
4279126	GRCh37/hg19 12p12.1(chr12:21687968-21710166)x1	Pathogenic
4529507	NG_016167.1:g.21559097_21559098ins[PP887427.1:g.1_1518]	Pathogenic
4702468	NM_021957.4(GYS2):c.1264C>T (p.Arg422Ter)	Pathogenic
4807181	NM_021957.4(GYS2):c.1209dup (p.Leu404fs)	Pathogenic
498897	NM_021957.4(GYS2):c.457del (p.Met152_Leu153insTer)	Pathogenic
686518	GRCh37/hg19 12p12.1(chr12:21685107-21774521)x1	Pathogenic
937499	NM_021957.4(GYS2):c.465del (p.Phe155fs)	Pathogenic
1223503	NM_021957.4(GYS2):c.122-8_186delinsATCAGA	Likely pathogenic
16053	NM_021957.4(GYS2):c.1472T>G (p.Met491Arg)	Likely pathogenic
1678032	NM_021957.4(GYS2):c.312del (p.Phe104fs)	Likely pathogenic
214532	NM_021957.4(GYS2):c.1427T>A (p.Ile476Asn)	Likely pathogenic
2161127	NM_021957.4(GYS2):c.942-2A>G	Likely pathogenic
2440667	NM_021957.4(GYS2):c.1753C>T (p.Gln585Ter)	Likely pathogenic
3065822	NM_021957.4(GYS2):c.1701_1704del (p.Thr568fs)	Likely pathogenic
3382249	NM_021957.4(GYS2):c.359_375del (p.Ile120fs)	Likely pathogenic
3574541	NM_021957.4(GYS2):c.948del (p.Asp317fs)	Likely pathogenic
3574542	NM_021957.4(GYS2):c.729C>A (p.Cys243Ter)	Likely pathogenic
3574543	NM_021957.4(GYS2):c.439C>T (p.Arg147Ter)	Likely pathogenic
3779718	NM_021957.4(GYS2):c.1463dup (p.Leu488fs)	Likely pathogenic

SpliceAI

2354 predictions. Top by Δscore:

Variant	Effect	Δscore
12:21539334:TAATA:T	acceptor_gain	1.0000
12:21539335:AATA:A	acceptor_gain	1.0000
12:21539336:ATA:A	acceptor_gain	1.0000
12:21539337:TA:T	acceptor_gain	1.0000
12:21539339:C:CC	acceptor_gain	1.0000
12:21539340:T:G	acceptor_loss	1.0000
12:21540406:TTA:T	donor_loss	1.0000
12:21540407:TAC:T	donor_loss	1.0000
12:21540408:A:AC	donor_gain	1.0000
12:21540409:C:CC	donor_gain	1.0000
12:21540409:CT:C	donor_gain	1.0000
12:21540409:CTCTG:C	donor_gain	1.0000
12:21540422:T:C	donor_gain	1.0000
12:21540460:T:A	donor_gain	1.0000
12:21546339:CATA:C	donor_loss	1.0000
12:21546340:ATAC:A	donor_loss	1.0000
12:21546341:TAC:T	donor_loss	1.0000
12:21546343:CC:C	donor_loss	1.0000
12:21558194:TTCTA:T	donor_loss	1.0000
12:21558195:TCTA:T	donor_loss	1.0000
12:21558196:CTA:C	donor_loss	1.0000
12:21558197:TA:T	donor_loss	1.0000
12:21558198:A:C	donor_loss	1.0000
12:21558309:TGTCG:T	acceptor_gain	1.0000
12:21558312:CG:C	acceptor_gain	1.0000
12:21558314:C:CC	acceptor_gain	1.0000
12:21558319:G:C	acceptor_gain	1.0000
12:21558319:G:GC	acceptor_gain	1.0000
12:21558321:A:AC	acceptor_gain	1.0000
12:21558321:A:C	acceptor_gain	1.0000

AlphaMissense

4632 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:21540425:C:A	W598C	1.000
12:21540425:C:G	W598C	1.000
12:21540427:A:G	W598R	1.000
12:21540427:A:T	W598R	1.000
12:21542543:C:T	G533E	1.000
12:21542584:G:C	C519W	1.000
12:21546353:A:G	Y514H	1.000
12:21546356:C:G	G513R	1.000
12:21546359:A:G	W512R	1.000
12:21546359:A:T	W512R	1.000
12:21562970:T:A	K337I	1.000
12:21562988:C:A	R331M	1.000
12:21563327:C:T	G281D	1.000
12:21574190:C:A	R211M	1.000
12:21576042:A:G	W107R	1.000
12:21576042:A:T	W107R	1.000
12:21580492:C:A	K51N	1.000
12:21580492:C:G	K51N	1.000
12:21580520:C:T	G42E	1.000
12:21540444:A:G	L592P	0.999
12:21540461:C:A	R586S	0.999
12:21540461:C:G	R586S	0.999
12:21542537:C:T	G535D	0.999
12:21542539:A:C	F534L	0.999
12:21542539:A:T	F534L	0.999
12:21542541:A:G	F534L	0.999
12:21542544:C:A	G533W	0.999
12:21542544:C:G	G533R	0.999
12:21542544:C:T	G533R	0.999
12:21542549:A:G	L531P	0.999

dbSNP variants (sampled 300 via entrez): RS1000002396 (12:21538143 A>C), RS1000047265 (12:21593361 T>G), RS1000135286 (12:21579157 C>G,T), RS1000156395 (12:21545763 G>A), RS1000173296 (12:21597512 G>A), RS1000205397 (12:21600381 G>C), RS1000210219 (12:21554491 C>T), RS1000211700 (12:21551647 T>A), RS1000241937 (12:21534445 A>G), RS1000242755 (12:21551348 T>C), RS1000268340 (12:21560320 G>A), RS1000309937 (12:21596864 CA>C), RS1000351336 (12:21579616 C>T), RS1000400151 (12:21557046 G>T), RS1000499666 (12:21562586 G>A)

Disease associations

OMIM: gene MIM:138571 | disease phenotypes: MIM:240600, MIM:232200, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
glycogen storage disorder due to hepatic glycogen synthase deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
glycogen storage disorder due to hepatic glycogen synthase deficiency	Definitive	AR

Mondo (3): glycogen storage disorder due to hepatic glycogen synthase deficiency (MONDO:0009414), disorder of glycogen metabolism (MONDO:0002412), schizophrenia (MONDO:0005090)

Orphanet (3): Glycogen storage disease due to hepatic glycogen synthase deficiency (Orphanet:2089), Glycogen storage disease (Orphanet:79201), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

18 total (19 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000737	Irritability
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001946	Ketosis
HP:0001998	Neonatal hypoglycemia
HP:0002151	Increased circulating lactate concentration
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0002919	Ketonuria
HP:0003076	Glycosuria
HP:0003077	Hyperlipidemia
HP:0003162	Fasting hypoglycemia
HP:0004322	Short stature
HP:0011024	Abnormality of the gastrointestinal tract
HP:0011998	Postprandial hyperglycemia
HP:0012734	Ketotic hypoglycemia
HP:0100753	Schizophrenia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004049_13	Cough in response to angiotensin-converting enzyme inhibitor drugs	2.000000e-07
GCST010083_352	Hemoglobin levels	9.000000e-09
GCST90002384_304	Hemoglobin	6.000000e-11
GCST90013407_69	Liver enzyme levels (gamma-glutamyl transferase)	5.000000e-20

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0004509	hemoglobin measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006008	Glycogen Storage Disease	C16.320.565.202.449; C18.452.648.202.449
C565485	Glycogen Storage Disease 0, Liver (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523243 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.39	EC50	4100	nM	CHEMBL4558600

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(1R,2R,4aS,6aR,6aS,6bR,8aR,10R,11R,12aR,14bS)-11-acetyloxy-1-hydroxy-10-[(E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoyl]oxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid	1612303: Activation of insulin-stimulated glycogen synthase in human HepG2 cells using [U-14C]UDP glucose as substrate preincubated for 18 hrs followed by insulin stimulation and measured after 15 mins by beta-counting method	ec50	4.1000	uM

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases expression, decreases reaction	3
Benzo(a)pyrene	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation, affects expression	2
bisphenol F	increases expression	1
methyleugenol	decreases expression	1
bisphenol A	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
obeticholic acid	increases expression	1
procyanidin B1	affects cotreatment, increases activity	1
p-coumaric acid	increases activity, affects cotreatment	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Acetaminophen	decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Endosulfan	decreases expression, decreases reaction	1
Estradiol	decreases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4411714	Binding	Activation of insulin-stimulated glycogen synthase in human HepG2 cells at MNTD using [U-14C]UDP glucose as substrate preincubated for 18 hrs followed by insulin stimulation and measured after 15 mins by beta-counting method relative to con	Bioactive Pentacyclic Triterpenes from the Root Bark Extract of Myrianthus arboreus, a Species Used Traditionally to Treat Type-2 Diabetes. — J Nat Prod

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety