EPM2A

Summary

EPM2A (EPM2A glucan phosphatase, laforin, HGNC:3413) is a protein-coding gene on chromosome 6q24.3, encoding Laforin, isoform 9 (B3EWF7).

This gene encodes a dual-specificity phosphatase and may be involved in the regulation of glycogen metabolism. The protein acts on complex carbohydrates to prevent glycogen hyperphosphorylation, thus avoiding the formation of insoluble aggregates. Loss-of-function mutations in this gene have been associated with Lafora disease, a rare, adult-onset recessive neurodegenerative disease, which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of insoluble particles called Lafora bodies, which are derived from glycogen.

Source: NCBI Gene 7957 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Lafora disease (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 472 total — 31 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 42
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_005670

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3413
Approved symbol	EPM2A
Name	EPM2A glucan phosphatase, laforin
Location	6q24.3
Locus type	gene with protein product
Status	Approved
Aliases	LDE, LD
Ensembl gene	ENSG00000112425
Ensembl biotype	protein_coding
OMIM	607566
Entrez	7957

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 11 protein_coding, 8 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay, 4 retained_intron

ENST00000367519, ENST00000435470, ENST00000450221, ENST00000461700, ENST00000489412, ENST00000496228, ENST00000611340, ENST00000638262, ENST00000638554, ENST00000638597, ENST00000638717, ENST00000638778, ENST00000638783, ENST00000639049, ENST00000639106, ENST00000639423, ENST00000639465, ENST00000639648, ENST00000639649, ENST00000639799, ENST00000639849, ENST00000639859, ENST00000640225, ENST00000640297, ENST00000640351, ENST00000640426, ENST00000640898, ENST00000640980

RefSeq mRNA: 9 — MANE Select: NM_005670 NM_001018041, NM_001360057, NM_001360064, NM_001360071, NM_001368129, NM_001368130, NM_001368131, NM_001368132, NM_005670

CCDS: CCDS5206, CCDS87452, CCDS87453, CCDS87454

Canonical transcript exons

ENST00000367519 — 4 exons

Exon	Start	End
ENSE00003610868	145635245	145635486
ENSE00003678033	145686122	145686296
ENSE00003842326	145735198	145735520
ENSE00003845265	145625305	145627693

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 95.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.9943 / max 61.0028, expressed in 1541 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76070	1.8783	962
76071	1.4165	730
76072	0.8998	400
76069	0.4828	223
76073	0.3170	145

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.29	gold quality
biceps brachii	UBERON:0001507	94.71	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.59	gold quality
gastrocnemius	UBERON:0001388	94.40	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.35	gold quality
skeletal muscle tissue	UBERON:0001134	94.31	gold quality
vastus lateralis	UBERON:0001379	94.20	gold quality
muscle of leg	UBERON:0001383	94.18	gold quality
muscle organ	UBERON:0001630	94.15	gold quality
quadriceps femoris	UBERON:0001377	93.81	gold quality
diaphragm	UBERON:0001103	92.70	gold quality
body of tongue	UBERON:0011876	92.39	gold quality
deltoid	UBERON:0001476	92.20	gold quality
muscle tissue	UBERON:0002385	91.69	gold quality
heart right ventricle	UBERON:0002080	91.56	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	90.78	gold quality
tibialis anterior	UBERON:0001385	90.11	gold quality
medial globus pallidus	UBERON:0002477	90.10	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.47	gold quality
gluteal muscle	UBERON:0002000	88.82	gold quality
saphenous vein	UBERON:0007318	88.68	gold quality
spinal cord	UBERON:0002240	88.67	gold quality
globus pallidus	UBERON:0001875	88.40	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.03	gold quality
lower esophagus	UBERON:0013473	87.95	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.34	gold quality
sperm	CL:0000019	87.07	gold quality
cardiac ventricle	UBERON:0002082	87.06	gold quality
mucosa of stomach	UBERON:0001199	87.01	gold quality
heart left ventricle	UBERON:0002084	87.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting EPM2A, 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-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-21-5P	99.46	70.54	1035
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-590-5P	99.25	70.76	930
HSA-MIR-4777-3P	99.15	68.92	626
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-2681-3P	98.18	65.28	577
HSA-MIR-1262	98.17	66.52	757
HSA-MIR-4701-3P	98.17	66.25	788
HSA-MIR-6736-5P	98.17	66.43	760
HSA-MIR-1180-5P	98.16	65.32	460
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-876-5P	97.99	68.49	1345
HSA-MIR-943	97.81	64.42	694
HSA-MIR-4689	96.97	65.79	1209
HSA-MIR-3156-5P	96.93	67.36	800
HSA-MIR-4540	96.90	67.46	473
HSA-MIR-3167	96.81	67.09	1236
HSA-MIR-6858-5P	96.05	64.59	1020

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Laforin is an active phosphatase; therefore, isoforms targeted to different cellular compartments might dephosphorylate and regulate distinct cellular substrates. (PMID:11883934)
• identification of mutations in EPM2A with phenotypes of 22 patients (14 families) and identification of two subsyndromes (PMID:12019207)
• The EPM2AIP1 gene was identified and characterized in a screen for laforin-interacting proteins with a human brain cDNA library; the specificity of the interaction was confirmed; subcellular colocalization of laforin and EPM2AIP1 protein was demonstrated (PMID:12782127)
• Laforin interacts with HIRPI5. (PMID:12915448)
• Up to 20% cases of LD are not genetically linked to chromosome 6. We report two sisters affected from bioptically diagnosed LD but without evidence of EPM2A mutation (PMID:14643920)
• encodes a 331 amino acid protein that contains an N-terminal carbohydrate-binding domain (CBD) and a C-terminal dual-specificity phosphatase domain. The CBD of laforin targets the protein to Lafora inclusion bodies. (PMID:14706656)
• Six novel mutations were identified, one of which is the first mutation specific to the cytoplasmic laforin isoform, implicating this isoform in disease pathogenesis. (PMID:14722920)
• Laforin is a Glycogen-Synthase-Kinase-3 Ser 9 phosphatase, and therefore capable of inactivating GS through GSK3. (PMID:16115820)
• Laforin does not dephosphorylate GSK3B (beta) in vitro, but possesses the unique ability to utilize a phosphorylated complex carbohydrate as a substrate and this function may be necessary for the maintenance of normal cellular glycogen. (PMID:16901901)
• Inactivation of Epm2a resulted in increased Wnt signaling and tumorigenesis (PMID:16959610)
• results demonstrate a critical role of dimerization in Laforin function and suggest an important new dimension in protein phosphatase function and in molecular pathogenesis of Lafora’s disease (PMID:16971387)
• Defects in laforin may lead to increased levels of misfolded and/or target proteins, which may eventually affect the physiological processes of the neuron, and likely to be the primary trigger in the physiopathology of lafora disease. (PMID:17337485)
• study concludse that considerable variability in the age at onset of Lafora disease can occur within families; identical mutations can be associated with the classic adolescent presentation, as well as late-onset cases (PMID:17509003)
• Laforin is conserved in all vertebrates and a small class of protists; it is not found in other organisms. Additionally, laforin is a functional equivalent of the plant phosphatase SEX4, and it may function to dephosphorylate complex carbohydrates. (PMID:17646401)
• Regulation of glycogen synthesis by the laforin-malin complex is modulated by the AMP-activated protein kinase pathway. (PMID:18029386)
• Laforin acts as a scaffold that allows the E3 ubiquitin ligase malin to ubiquitinate protein targeting to glycogen (PTG). These results suggest an additional mechanism, involving laforin and malin, in regulating glycogen metabolism. (PMID:18070875)
• Results suggest that the altered subcellular localization of mutant proteins of the EPM2A and NHLRC1 genes could be one of the molecular bases of the Lafora disease phenotype. (PMID:18311786)
• EPM2A regulated by alternative splicing plays roles in Lafora progressive myoclonus epilepsy. (PMID:18617530)
• Laforin and malin interact with misfolded proteins and promote their degradation through the ubiquitin-proteasome system. (PMID:19036738)
• phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity. (PMID:19171932)
• Mutations of EPM2A formed aggregates and elicited endoplasm reticulum stress in neuronal cell. (PMID:19403557)
• laforin and malin play a role protecting cells from ER-stress, likely contributing to the elimination of unfolded proteins (PMID:19529779)
• Laforin regulates autophagy. (PMID:20453062)
• These results suggest that the modification introduced by the laforin-malin complex could affect the subcellular distribution of AMPK beta subunits. (PMID:20534808)
• study described several novel mutations of EPM2A and NHLRC1 and brought additional data to genetic epidemiology of Lafora disease (LD); emphasized the high mutation rate in patients with classical LD as well as the high negativity rate of skin biopsy (PMID:20738377)
• Genetic analysis showed a novel c.659 T>A mutation on exon 3 of the EPM2A gene, in a patient with Lafora’s disease. (PMID:21371719)
• Laforin and malin are defective in Lafora disease (LD), a neurodegenerative disorder associated with epileptic seizures (PMID:21652633)
• results of the present study suggest that phosphorylation of laforin-Ser(25) by AMPK provides a mechanism to modulate the interaction between laforin and malin (PMID:21728993)
• laforin monomer is the dominant form of the protein and that it contains phosphatase activity. (PMID:21887368)
• glycogen phosphorylation can be considered a catalytic error and laforin a repair enzyme. (PMID:21930129)
• alternative splicing could possibly be one of the mechanisms by which EPM2A may regulate the cellular functions of the proteins it codes for (PMID:22036712)
• This study identified that EPM2 gene mutations leading to Lafora disease in six Turkish families. (PMID:22047982)
• Studies indicate that laforin directly dephosphorylates glycogen. (PMID:22364389)
• Malin forms a functional complex with laforin. This complex promotes the ubiquitination of proteins involved in glycogen metabolism and misregulation of pathways involved in this process results in Lafora body formation. (Review) (PMID:22815132)
• A new novel mutation of the EPM2A gene is identified that causes Lafora disease. (PMID:23313408)
• This study identified the flexibility of K87A mutated laforin structure, with replacement of acidic amino acid to aliphatic amino acid in functional carbohydrate binding module domain, have more impact in abolishing glycogen binding that favors Lafora disease. (PMID:23904258)
• These results suggest that cysteine 329 is specifically involved in the dimerization process of laforin. (PMID:23922729)
• Polyglucosan body degradation requires a protein assembly that includes laforin and malin. (PMID:24068615)
• Studied the role of conformational changes in human laforin structure due to existing single mutation W32G and prepared double mutation W32G/K87A related to loss of glycogen binding. (PMID:24770803)
• This study suggest that variations in phenotypes of EPM2A-deficient Lafora disease. (PMID:25246353)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	epm2a	ENSDARG00000059044
mus_musculus	Epm2a	ENSMUSG00000055493
rattus_norvegicus	Epm2a	ENSRNOG00000040242

Paralogs (31): DUSP13B (ENSG00000079393), DUSP12 (ENSG00000081721), SSH1 (ENSG00000084112), DUSP3 (ENSG00000108861), PTPMT1 (ENSG00000110536), DUSP16 (ENSG00000111266), DUSP22 (ENSG00000112679), DUSP1 (ENSG00000120129), DUSP4 (ENSG00000120875), STYXL1 (ENSG00000127952), DUSP9 (ENSG00000130829), DUSP26 (ENSG00000133878), DUSP5 (ENSG00000138166), DUSP6 (ENSG00000139318), SSH2 (ENSG00000141298), DUSP10 (ENSG00000143507), DUSP15 (ENSG00000149599), DUSP2 (ENSG00000158050), KASH5 (ENSG00000161609), DUSP19 (ENSG00000162999), DUSP7 (ENSG00000164086), DUSP18 (ENSG00000167065), SSH3 (ENSG00000172830), DUSP8 (ENSG00000184545), DUSP28 (ENSG00000188542), DUSP29 (ENSG00000188716), DUSP21 (ENSG00000189037), STYX (ENSG00000198252), STYXL2 (ENSG00000198842), DUSP14 (ENSG00000276023), DUSP13A (ENSG00000293543)

Protein

Protein identifiers

Laforin, isoform 9 — B3EWF7 (reviewed: B3EWF7, O95278)

All UniProt accessions (8): O95278, A0A1W2PP62, A0A1W2PPJ6, A0A1W2PPT8, A0A1W2PQ84, A0A1W2PRC9, A0A1W2PRS5, H0Y7S8

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with isoform 1 and isoform 2.

Subcellular location. Nucleus.

Miscellaneous. Produced by alternative initiation. Arises due to the use of an alternative initiation codon in exon 1 out of frame with isoform 1 and results in a completely different isoform.

Isoforms (8)

UniProt ID	Names	Canonical?
B3EWF7-1	9, POCR	yes
O95278-1	1, A, LDH1, Laf331
O95278-2	2, B, C-terISO, Laf317
O95278-4	4, Laf152
O95278-5	5, Laf224
O95278-6	6, Laf88
O95278-7	7, Laf177
O95278-8	8

RefSeq proteins (9): NP_001018051, NP_001346986, NP_001346993, NP_001347000, NP_001355058, NP_001355059, NP_001355060, NP_001355061, NP_005661* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000340	Dual-sp_phosphatase_cat-dom	Domain
IPR000387	Tyr_Pase_dom	Domain
IPR002044	CBM20	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR013784	Carb-bd-like_fold	Homologous_superfamily
IPR016130	Tyr_Pase_AS	Active_site
IPR020422	TYR_PHOSPHATASE_DUAL_dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR034831	CBM20_laforin	Domain
IPR042942	Laforin	Family
IPR045204	DSP_laforin-like	Domain

Pfam: PF00686, PF00782

Enzyme classification (BRENDA):

• EC 3.1.3.16 — protein-serine/threonine phosphatase (BRENDA: 92 organisms, 641 substrates, 468 inhibitors, 127 Km, 67 kcat entries)

Substrate kinetics (BRENDA)

59 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.023–0.862	22
4-NITROPHENYL PHOSPHATE	0.0028–12.7	13
P-NITROPHENYL PHOSPHATE	3–200	11
RRAPTVA	0.058–1.954	4
PHOSPHOCASEIN	0.0001–0.002	3
PHOSPHOHISTONE	0.0023–0.0723	3
PHOSPHORYLATED MYOSIN LIGHT CHAIN PEPTIDE	0.01–0.11	3
PHOSPHOSERINE-MYELIN BASIC PROTEIN	0.0004–0.022	3
DLDVPIPGRFDRRVSVAAE	0.0006–0.0138	2
DLDVPIPGRFDRRVY(P)VAAE	0.0025–0.023	2
PHOSPHORYLASE A	0.004–0.021	2
RRA(PT)VA	0.0536–0.308	2
80S-RIBOSOME	0.0027	1
AAAPTVA	0.206	1
AGPALSPVPPV	0.357	1

Catalyzed reactions (Rhea), 3 shown:

• O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate (RHEA:10684)
• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate (RHEA:47004)

UniProt features (114 total): mutagenesis site 27, sequence variant 21, helix 15, strand 14, splice variant 9, binding site 8, region of interest 4, sequence conflict 4, compositionally biased region 3, chain 2, domain 2, site 1, modified residue 1, short sequence motif 1, active site 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4R30	X-RAY DIFFRACTION	2.3
4RKK	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-B3EWF7-F1	34.25	0.00
AF-O95278-F1	95.93	0.94

Functional residue map

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

Catalytic / active sites (2): 329 (required for homodimerization); 266 (phosphocysteine intermediate)

Ligand- & substrate-binding residues (8): 241; 267–272; 304; 32; 87; 103–107; 197; 235

Post-translational modifications (1): 25

Mutagenesis-validated functional residues (27):

Position	Phenotype
8	loss of phosphatase activity. no effect on glycogen binding.
25	partial loss of phosphatase activity. abolishes homodimerization. abolishes interaction with nhlrc1, ppp1r3c and prkaa2.
25	partial loss of phosphatase activity. increases interaction with nhlrc1. does not affect interaction with nhlrc1, ppp1r3
87	loss of phosphatase activity. abolishes glycogen binding.
99	strongly reduces phosphatase activity. strongly reduces glycogen binding.
109–110	no effect on homodimerization or carbohydrate binding. decreased phosphatase activity.
123	no effect on homodimerization or carbohydrate binding. decreased phosphatase activity.
126	strongly decreased phosphatase activity. no effect on glycogen binding.
142	strongly decreased phosphatase activity. no effect on glycogen binding.
168	abolishes interaction with nhlrc1.
169	no effect on homodimerization or carbohydrate binding. decreased phosphatase activity.
169	no effect on phosphatase activity.
171	no effect on phosphatase activity.
187	abolishes interaction with nhlrc1.
194	does not affect interaction with nhlrc1, ppp1r3c or prkaa2.
197	strongly decreased phosphatase activity. no effect on glycogen binding.
205	no effect on homodimerization or carbohydrate binding. decreased phosphatase activity.
235	complete loss of phosphatase activity. does not affect glycogen binding.
236	complete loss of phosphatase activity. no effect on glycogen binding.
250	no effect on homodimerization or carbohydrate binding. decreased phosphatase activity.
251	impairs protein stability. strongly reduces phosphatase activity. no effect on glycogen binding.
266	complete loss of phosphatase activity. does not affect glycogen binding. does not affect self-interaction. increases the
272	complete loss of phosphatase activity.
321	impairs protein stability. strongly reduces phosphatase activity. no effect on glycogen binding.
329–331	fails to homodimerize. does not affect carbohydrate binding or phosphatase activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3322077	Glycogen synthesis
R-HSA-3785653	Myoclonic epilepsy of Lafora

MSigDB gene sets: 318 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_COGNITION, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GOBP_BEHAVIOR, GOBP_VACUOLE_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_REGULATION_OF_PHOSPHATASE_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_PHOSPHORYLATION, GOBP_NEUROGENESIS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY

GO Biological Process (30): positive regulation of macroautophagy (GO:0016239), negative regulation of TOR signaling (GO:0032007), autophagosome assembly (GO:0000045), regulation of cell growth (GO:0001558), glycogen metabolic process (GO:0005977), glycogen biosynthetic process (GO:0005978), protein dephosphorylation (GO:0006470), calcium ion transport (GO:0006816), mitochondrion organization (GO:0007005), negative regulation of gene expression (GO:0010629), negative regulation of phosphatase activity (GO:0010923), glial cell proliferation (GO:0014009), L-glutamate transmembrane transport (GO:0015813), Wnt signaling pathway (GO:0016055), dephosphorylation (GO:0016311), regulation of protein ubiquitination (GO:0031396), negative regulation of dephosphorylation (GO:0035305), peptidyl-tyrosine dephosphorylation (GO:0035335), regulation of protein import into nucleus (GO:0042306), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of cell cycle (GO:0045786), carbohydrate phosphorylation (GO:0046835), habituation (GO:0046959), regulation of proteasomal protein catabolic process (GO:0061136), regulation of protein localization to plasma membrane (GO:1903076), phosphate-containing compound metabolic process (GO:0006796), autophagy (GO:0006914), nervous system development (GO:0007399), negative regulation of metabolic process (GO:0009892), regulation of gene expression (GO:0010468)

GO Molecular Function (15): alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity (GO:0004373), protein serine/threonine phosphatase activity (GO:0004722), protein tyrosine phosphatase activity (GO:0004725), phosphatase activity (GO:0016791), carbohydrate phosphatase activity (GO:0019203), carbohydrate binding (GO:0030246), protein homodimerization activity (GO:0042803), protein dimerization activity (GO:0046983), glycogen binding (GO:2001069), starch binding (GO:2001070), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787), polysaccharide binding (GO:0030247), identical protein binding (GO:0042802)

GO Cellular Component (12): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), dendrite (GO:0030425), perikaryon (GO:0043204), cytoplasmic side of rough endoplasmic reticulum membrane (GO:0098556), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Glycogen metabolism	1
Glycogen storage diseases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
phosphatase activity	3
dephosphorylation	2
phosphoprotein phosphatase activity	2
binding	2
protein binding	2
polysaccharide binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
positive regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
energy reserve metabolic process	1
glucan metabolic process	1
glycogen metabolic process	1
glucan biosynthetic process	1
protein modification process	1
metal ion transport	1
organelle organization	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
regulation of phosphatase activity	1
negative regulation of dephosphorylation	1
negative regulation of hydrolase activity	1
cell population proliferation	1
gliogenesis	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

4 interactions, top by confidence:

A	B	Type	Score
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A1W2PPE3, A0A3B3IS91, A0A6I8MX38, A0A6I8PU40, A8MTW9, B1AH88, B3EWF7, C0HLS1, C0HMD6, H3BQW9, I3L0S3, I3L1E1, O70738, O75638, P03289, P0C880, P0DI83, P11300, P13985, P16807, P29164, P33485, P59091, P80612, Q01480, Q01900, Q3SYB3, Q5JLA7, Q5SY85, Q5T4H9, Q63003, Q6EEV4, Q6VB84, Q86SI9, Q8N1I8, Q8N1X5, Q8N319, Q8N6K4, Q8N6U2, Q8N726

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	13
Uncertain significance	214
Likely benign	151
Benign	19

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068477	NM_005670.4(EPM2A):c.302-2A>G	Pathogenic
1075527	NM_005670.4(EPM2A):c.108_139del (p.Ala37fs)	Pathogenic
1322827	NM_005670.4(EPM2A):c.322del (p.Arg108fs)	Pathogenic
1418032	NM_005670.4(EPM2A):c.759_760insATGCA (p.Ala254fs)	Pathogenic
1451802	NM_005670.4(EPM2A):c.258C>G (p.Tyr86Ter)	Pathogenic
1454028	NM_005670.4(EPM2A):c.934dup (p.Arg312fs)	Pathogenic
1456100	NC_000006.11:g.(?146056334)(146056634_?)del	Pathogenic
1459452	NC_000006.11:g.(?145948552)(145956642_?)del	Pathogenic
1510680	NM_005670.4(EPM2A):c.301+1G>T	Pathogenic
1761008	NM_005670.4(EPM2A):c.788_791dup (p.His265fs)	Pathogenic
1761009	NM_005670.4(EPM2A):c.788_792delinsCCCTTCTGCCCAC (p.Tyr263fs)	Pathogenic
2020620	NM_005670.4(EPM2A):c.301+2T>C	Pathogenic
2024510	NM_005670.4(EPM2A):c.96G>A (p.Trp32Ter)	Pathogenic
205431	NM_005670.4(EPM2A):c.166G>T (p.Glu56Ter)	Pathogenic
205446	NM_005670.4(EPM2A):c.303_476+1del	Pathogenic
2136482	NM_005670.4(EPM2A):c.256T>G (p.Tyr86Asp)	Pathogenic
2734962	NM_005670.4(EPM2A):c.861G>A (p.Trp287Ter)	Pathogenic
3101	NM_005670.4(EPM2A):c.335dup (p.Tyr112Ter)	Pathogenic
3776209	NM_005670.4(EPM2A):c.43_159del (p.Gly15_Ala53del)	Pathogenic
3776856	NM_005670.4(EPM2A):c.336C>A (p.Tyr112Ter)	Pathogenic
3776900	NM_005670.4(EPM2A):c.259A>T (p.Lys87Ter)	Pathogenic
3776909	NM_005670.4(EPM2A):c.243_246del (p.Asp82fs)	Pathogenic
423471	NM_005670.4(EPM2A):c.466_469dup (p.Tyr157fs)	Pathogenic
433103	NM_005670.4(EPM2A):c.314A>G (p.His105Arg)	Pathogenic
462911	NC_000006.12:g.(?145686102)(145686316_?)del	Pathogenic
4718816	NM_005670.4(EPM2A):c.920_921dup (p.Glu308fs)	Pathogenic
4805338	NM_005670.4(EPM2A):c.934del (p.Arg312fs)	Pathogenic
830902	NC_000006.12:g.(?145625675)(145635506_?)del	Pathogenic
862225	NM_005670.4(EPM2A):c.74C>A (p.Ser25Ter)	Pathogenic
872146	NM_005670.4(EPM2A):c.269_275del (p.Lys90fs)	Pathogenic

SpliceAI

1055 predictions. Top by Δscore:

Variant	Effect	Δscore
6:145627692:GCC:G	acceptor_loss	1.0000
6:145627694:CTGC:C	acceptor_loss	1.0000
6:145627695:T:A	acceptor_loss	1.0000
6:145686293:TTGC:T	acceptor_gain	1.0000
6:145686295:GCCT:G	acceptor_loss	1.0000
6:145686297:C:CC	acceptor_gain	1.0000
6:145686297:CTAG:C	acceptor_loss	1.0000
6:145686298:T:G	acceptor_loss	1.0000
6:145686303:C:CT	acceptor_gain	1.0000
6:145627690:CGGC:C	acceptor_gain	0.9900
6:145627694:C:CC	acceptor_gain	0.9900
6:145627698:G:T	acceptor_gain	0.9900
6:145635239:CCTTA:C	donor_loss	0.9900
6:145635240:CTTA:C	donor_loss	0.9900
6:145635241:TTA:T	donor_loss	0.9900
6:145635242:TACC:T	donor_loss	0.9900
6:145635243:A:T	donor_loss	0.9900
6:145671292:G:C	donor_gain	0.9900
6:145686116:TTTTA:T	donor_loss	0.9900
6:145686117:TTTAC:T	donor_loss	0.9900
6:145686118:TTA:T	donor_loss	0.9900
6:145686119:TA:T	donor_loss	0.9900
6:145686121:C:CA	donor_loss	0.9900
6:145686180:T:TA	donor_gain	0.9900
6:145686294:TGC:T	acceptor_gain	0.9900
6:145686295:GC:G	acceptor_gain	0.9900
6:145686296:CC:C	acceptor_gain	0.9900
6:145686304:A:T	acceptor_gain	0.9900
6:145735200:T:A	donor_gain	0.9900
6:145627689:TCGGC:T	acceptor_gain	0.9800

AlphaMissense

2156 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001552 (6:145473831 T>C), RS1000002298 (6:145482372 T>C), RS1000041959 (6:145608941 C>G,T), RS1000044911 (6:145393519 A>T), RS1000046411 (6:145658581 A>G), RS1000052350 (6:145527277 A>G), RS1000070971 (6:145658988 G>A), RS1000071777 (6:145679999 C>T), RS1000076502 (6:145641181 C>T), RS1000077291 (6:145393221 C>A,T), RS1000118798 (6:145395722 G>A), RS1000119747 (6:145644942 T>C), RS1000126987 (6:145476711 T>C), RS1000135781 (6:145423653 A>T), RS1000149858 (6:145434414 C>T)

Disease associations

OMIM: gene MIM:607566 | disease phenotypes: MIM:254800, MIM:254780, MIM:116200, MIM:117100

GenCC curated gene-disease

Disease	Classification	Inheritance
Lafora disease	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Lafora disease	Definitive	AR

Mondo (8): progressive myoclonus epilepsy (MONDO:0020074), Lafora disease (MONDO:0009697), myoclonic epilepsy of Lafora 1 (MONDO:0958199), congenital nervous system disorder (MONDO:0002320), microcephaly (MONDO:0001149), cataract (MONDO:0005129), intellectual disability (MONDO:0001071), self-limited epilepsy with centrotemporal spikes (MONDO:0007295)

Orphanet (5): Progressive myoclonic epilepsy type 1 (Orphanet:308), Progressive myoclonic epilepsy (Orphanet:98261), Lafora disease (Orphanet:501), Self-limited epilepsy with centrotemporal spikes (Orphanet:1945), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000572	Visual loss
HP:0000709	Psychosis
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000726	Dementia
HP:0000992	Cutaneous photosensitivity
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001312	Giant somatosensory evoked potentials
HP:0001336	Myoclonus
HP:0001399	Hepatic failure
HP:0002069	Bilateral tonic-clonic seizure
HP:0002100	Recurrent aspiration pneumonia
HP:0002121	Generalized non-motor (absence) seizure
HP:0002123	Generalized myoclonic seizure
HP:0002133	Status epilepticus
HP:0002186	Apraxia
HP:0002315	Headache
HP:0002344	Progressive neurologic deterioration
HP:0002360	Sleep disturbance
HP:0002367	Visual hallucination
HP:0002384	Focal impaired awareness seizure
HP:0002521	Hypsarrhythmia
HP:0002540	Inability to walk

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003773_7	Loneliness (multivariate analysis)	2.000000e-06
GCST004136_34	Methadone dose in opioid dependence	7.000000e-06
GCST004599_46	Mean platelet volume	8.000000e-09
GCST005115_1	Response to mepolizumab in severe asthma	1.000000e-06
GCST90002395_490	Mean platelet volume	7.000000e-17

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007865	loneliness measurement
EFO:0007907	methadone dose measurement
EFO:0008459	response to mepolizumab

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002386	Cataract	C11.510.245
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D020192	Lafora Disease	C10.228.140.490.375.130.650.500; C10.228.140.490.493.063.650.500; C10.574.500.529; C16.320.400.480
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D020191	Myoclonic Epilepsies, Progressive	C10.228.140.490.375.130.650; C10.228.140.490.493.063.650

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1415744	Efficacy	3	chlorpromazine;clozapine;haloperidol;olanzapine;quetiapine;risperidone;trifluoperazine	Schizophrenia

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1415744	EPM2A	3	2.50	1	chlorpromazine;clozapine;haloperidol;olanzapine;quetiapine;risperidone;trifluoperazine

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
Benzo(a)pyrene	decreases expression	2
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
Magnetite Nanoparticles	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00273221	PHASE4	UNKNOWN	Combined Phacotube vs Phacotrabeculectomy:A Randomized Controlled Trial
NCT00312299	PHASE4	COMPLETED	Posterior Capsule Opacification Study
NCT00345046	PHASE4	COMPLETED	A Comparison of Three Different Formulations of Prednisolone Acetate 1%
NCT00347243	PHASE4	COMPLETED	Wavefront Analisys and Contrast Sensitivity of Spherical and Aspherical Intraocular Lenses
NCT00347503	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients
NCT00348244	PHASE4	COMPLETED	Ketorolac vs. Steroid in the Prevention of CME
NCT00348270	PHASE4	COMPLETED	Comparison of the Quality of Vision Provided by AMO Tecnis Z9000 and Alcon Laboratories MA60 Acrysof Posterior Chamber Intraocular Lenses
NCT00348582	PHASE4	COMPLETED	Acular LS vs. Nevanac in Post op Inflammation Following Cataract Surgery
NCT00348621	PHASE4	COMPLETED	A Study of Interventions to Reduce Disability From Visual Loss in Nursing Home Residents
NCT00349583	PHASE4	COMPLETED	Efficacy of Topical Cyclosporine Versus Tears for Improving Visual Outcomes Following Multifocal IOL Implantation
NCT00355446	PHASE4	COMPLETED	Bioavailability of Bimatoprost Ophthalmic Solution in Human Aqueous.
NCT00386438	PHASE4	COMPLETED	Efficacy of Honan Balloon in Intraocular Pressure Reduction Before Phacoemulsification
NCT00392275	PHASE4	COMPLETED	Penetrance of Third Generation Fluoroquinolones in Eyes With Functioning Filtering Blebs
NCT00428363	PHASE4	COMPLETED	Effect of Optic Edge Design in a Silicone Intraocular Lens on Posterior Capsule Opacification
NCT00449267	PHASE4	COMPLETED	Aurolab Hydrophobic Foldable Intraocular Lens Study
NCT00459303	PHASE4	COMPLETED	Comparison of Functional Vision Provided by AMO Tecnis Z9000 and Alcon SA60AT Acrysof
NCT00469690	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients: Trough Drug Effects
NCT00576485	PHASE4	COMPLETED	Spherical Aberration and Contrast Sensitivity in IOLs
NCT00612729	PHASE4	COMPLETED	Light Filters in Intraocular Lenses (IOLs) and Its Influence on Colour and Contrast Vision.
NCT00612781	PHASE4	COMPLETED	Yellow Versus White Study
NCT00630019	PHASE4	COMPLETED	Ocular Tissue Levels of 1.5% Levofloxacin Ophthalmic Solution Compared to an Active Comparator
NCT00673803	PHASE4	COMPLETED	Influence of Two Different Preloaded Intraocular Lens (IOLs) on Posterior Capsule Opacification
NCT00684138	PHASE4	COMPLETED	ACRYSOF® ReSTOR® Aspheric +3.0 D Add Power Intraocular Lens (IOL)
NCT00698724	PHASE4	COMPLETED	Comparing Optical Coherence Tomography (OCT) and Visual Acuity Outcomes in Subjects Undergoing Cataract Surgery, Who Receive Xibrom Ophthalmic Solution and Standard Presurgical Care vs. Xibrom Ophthalmic Solution Plus Prednisolone Acetate 1% and Standard Presurgical Care
NCT00710905	PHASE4	TERMINATED	Visual Function With Contralateral AcrySof® ReSTOR® Aspheric SN6AD1 and SN6AD3
NCT00710931	PHASE4	COMPLETED	Visual Function With Bilateral AcrySof® ReSTOR® Aspheric SN6AD1
NCT00711347	PHASE4	COMPLETED	Intraoperative Floppy Iris Syndrome
NCT00712244	PHASE4	COMPLETED	DisCoVisc Versus DuoVisc, Healon5 and AmVisc Plus
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00719732	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof ReSTOR Aspheric +3
NCT00721253	PHASE4	COMPLETED	Visual Outcomes of Subjects Bilaterally Implanted With ReSTOR Aspheric +4 vs. Tecnis or Acri.LISA
NCT00731640	PHASE4	COMPLETED	Contralateral ReSTOR / Monofocal or Phakic Eye
NCT00732030	PHASE4	COMPLETED	Low Cylinder Toric
NCT00758199	PHASE4	COMPLETED	Determination of Optimum Duration of Treatment With Bromfenac (Xibrom) Eyedrops Following Cataract Surgery
NCT00760058	PHASE4	WITHDRAWN	Visual Outcome and Visual Quality After Bilateral Implantation of the AcrySof® IQ IOL Compared to MI60® and Tecnis® IOL
NCT00760487	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof® Toric Natural Intraocular Lens
NCT00761488	PHASE4	WITHDRAWN	Recommendations for Monitoring Clinical Experience Following Implantation of the AcrySof® Toric
NCT00763360	PHASE4	COMPLETED	To Compare the Ability of DiscoVisc® OVD to Protect the Corneal Endothelium and Maintain Anterior Chamber Space With Healon® and Amvisc® PLUS During Cataract Surgery.
NCT00786370	PHASE4	COMPLETED	Dexmedetomidine vs. Propofol for Cataract Surgery
NCT00786565	PHASE4	COMPLETED	Clinical Evaluation of a New Aspheric Intraocular Lens.