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FLASH GENE

Symbol

EPM2A

contributors: mct - updated : 23-07-2015

HGNC name	epilepsy, progressive myoclonus type 2A, Lafora disease (laforin)
HGNC id	3413

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	EPM2A myoclonic epilepsy, progressive, Lafora type 2A
Location	6q24.3      Physical location : 145.946.445 - 146.056.991
Synonym name	laforin
	progressive myoclonus epilepsy with polyglucosan bodies
	LAFPTPase
Synonym symbol(s)	MELF, LD, LDE, EPM2
EC.number	3.1.1.48, 3.1.3.16

DNA

TYPE	functioning gene
SPECIAL FEATURE	head to head
STRUCTURE	110.55 kb     4 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	alternative splicing in the 5' and 3' end regions,transcripts group A,B,C,D (PMID: 9931343)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005670 4 - 3474 NP_005661 38 331 - 2008 18617530 also called EPM2A or laf331 using exons 4a, 1, 2, 3, 4 predominantly cytoplasmic with laf317 form dimers dual-specificity phosphatase NM_001018041 5 - 1711 NP_001018051 - 317 - 2008 18617530 also called EPM2B or laf317 using exons 4b, 1, 2, 3, 4b localized both in nucleus and cytoplasm with laf331 form dimers inactive phosphatase that competes with laf331 for the substrate and regulates the activity of laf331 by forming heterodimers interacting with malin (degraded by malin, NHLRC1) variant 3 - splicing 2800 isoform 3 - 250 brain 1999 9931343 also called EMP2A1 variant 4 - splicing 1030 isoform 4 - 236 brain 1999 9931343

EXPRESSION

Type

widely

constitutive of

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart         Digestive liver         Endocrine neuroendocrine pituitary     highly Lymphoid/Immune lymph node       highly Reproductive male system prostate     moderately Respiratory lung       moderately Skin/Tegument skin         Urinary kidney       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier/lining       Muscular striatum skeletal     Nervous central

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	carbohydrate binding domain (CB-D) at the N-terminus, critical for association with glycogen, and targeting the protein to Lafora inclusion bodies (only phosphatase in the animal kingdom that contains a carbohydrate-binding module)
	dual specificity phosphatase catalytic domain (DSPD) at the C-terminus

conjugated

PhosphoP

mono polymer

monomer , dimer

HOMOLOGY

interspecies	homolog to murine Epm2a
	homolog to C.elegans W01a11.1

Homologene

FAMILY	protein-tyrosine phosphatase family
	family of glucan phosphatases

CATEGORY

enzyme , secretory , receptor membrane tyrosine phosphatase

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum ,rough,smooth
	intracellular,cytoplasm,cytosolic
text	localized in dendrites but not in axons of neurons
	co-localize with EPM2B in endoplasmic reticulum (ER)

basic FUNCTION	a polysaccharide phosphatase, involved in translational regulation and in protein amino acid dephosphorylation
	involved in the regulation of glycogen metabolism throught the interaction with PP1R3C
	involved in glycogen metabolic pathway regulating the disposal of pathogenic polyglucosan inclusions
	detecting polyglucosan appearances during glycogen synthesis and initiating mechanisms to downregulate glycogen synthase
	dual specificity phosphatase that dephosphorylates complex carbohydrates
	having functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen
	regulates autophagy via the mammalian target of rapamycin kinase-dependent pathway
	modulates autophagy either at the level of TSC2 or above this protein
	regulator of insulin sensitivity, and this phosphatase is a potential novel component of the insulin signaling cascade
	laforin monomer is the dominant form of the protein and it contains phosphatase activity
	role of the EPM2A/NHLRC1 complex in the activation of autophagy via regulation of the PI3KC3 complex that explain the defect in autophagy described in Lafora disease

CELLULAR PROCESS

protein, translation regulation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

carbohydrate

signaling

glycogen metabolism, ubiquitin-proteasomal pathway

a component	EPM2A–NHLRC1 complex is a novel player in the neuronal response to misfolded proteins
	prevalently exists as a monomer with a small dimer fraction
	EPM2A–NHLRC1 complex negatively regulates glycogen synthesis by modulating cellular glucose uptake via glucose transporters
	a functional EPM2A–NHLRC1 complex plays a critical role in disrupting Lafora bodies and relieving ER stress, implying that a causative pathogenic mechanism underlies their deficiency in Lafora disease

INTERACTION

DNA

RNA

small molecule	other,
	binding polyglucosans

protein	with HIRIP5 (dephosphorylation of HIRIP5)
	with PPAR3C (binding with EPM2A critical for its function)
	binds glycogen, but also starch, amylose and cyclodextrin
	interacting with malin, through their middle portions (malin degrading the laforin)
	glycogen, as well as amylopectin, is a substrate for laforin
	interacts with proteins known to be involved in glycogen metabolism and rule out several of these proteins as potential substrates
	interact with misfolded proteins and promote its degradation through the ubiquitin–proteasome system
	critical partner for malin cellular functions
	NHLRC1 functions to regulate EPM2A and NHLRC1 deficiency at least in part causes Lafora bodies (LB) and Lafora disease (LD) through increased EPM2A binding to glycogen
	EPM2A-principle function is to control glycogen chain lengths, in a NHLRC1-dependent fashion, and loss of this control underlies LAFORA disease

cell & other

REGULATION

Phosphorylated by

Ser(25) is phosphorylated by AMPK

ASSOCIATED DISORDERS

corresponding disease(s)

EPM2A

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurology neurodegenerative   could be with NHLRC1 potential therapeutic targets for neurodegenerative disorders associated with cytotoxic proteins

ANIMAL & CELL MODELS

mice lacking laforin (epm2a-/-) have enhanced insulin response leading to altered whole-body energy balance