EPM2A epilepsy, progressive myoclonus type 2A, Lafora disease (laforin) [Homo sapiens] - Gene

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Summary

Official Symbol: EPM2Aprovided by HGNC
Official Full Name: epilepsy, progressive myoclonus type 2A, Lafora disease (laforin)provided by HGNC
Primary source: HGNC:3413
Locus tag: RP1-28C20.2
See related: Ensembl:ENSG00000112425; HPRD:06345; MIM:607566; Vega:OTTHUMG00000015747
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: EPM2; MELF
Summary: This gene encodes a dual-specificity phosphatase that associates with polyribosomes. The encoded protein may be involved in the regulation of glycogen metabolism. Mutations in this gene have been associated with myoclonic epilepsy of Lafora. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

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Genomic context

Location :: 6q24

Sequence :: Chromosome: 6; NC_000006.11 (145946440..146056991, complement)

See EPM2A in Epigenomics, MapViewer

Chromosome 6 - NC_000006.11 Genomic Context describing neighboring genes

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Genomic regions, transcripts, and products

Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

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Bibliography

GeneRIFs: Gene References Into Functions What's a GeneRIF?

alternative splicing could possibly be one of the mechanisms by which EPM2A may regulate the cellular functions of the proteins it codes for
Title: Identification and characterization of novel splice variants of the human EPM2A gene mutated in Lafora progressive myoclonus epilepsy.
Genetic analysis showed a novel c.659 T>A mutation on exon 3 of the EPM2A gene, in a patient with Lafora's disease.
Title: A novel exon 3 mutation in a Tunisian patient with Lafora's disease.
laforin monomer is the dominant form of the protein and that it contains phosphatase activity.
Title: Laforin, a dual specificity phosphatase involved in Lafora disease, is present mainly as monomeric form with full phosphatase activity.
Laforin and malin are defective in Lafora disease (LD), a neurodegenerative disorder associated with epileptic seizures
Title: Malin and laforin are essential components of a protein complex that protects cells from thermal stress.
glycogen phosphorylation can be considered a catalytic error and laforin a repair enzyme.
Title: Are there errors in glycogen biosynthesis and is laforin a repair enzyme?
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
Title: Laforin, a dual-specificity phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase.
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
Title: Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease.
These results suggest that the modification introduced by the laforin-malin complex could affect the subcellular distribution of AMPK beta subunits.
Title: The laforin-malin complex, involved in Lafora disease, promotes the incorporation of K63-linked ubiquitin chains into AMP-activated protein kinase beta subunits.
Laforin regulates autophagy.
Title: Laforin, the most common protein mutated in Lafora disease, regulates autophagy.
laforin and malin play a role protecting cells from ER-stress, likely contributing to the elimination of unfolded proteins
Title: Increased endoplasmic reticulum stress and decreased proteasomal function in lafora disease models lacking the phosphatase laforin.

Submit: New GeneRIF Correction See all (32)

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Phenotypes

Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Epilepsy, progressive myoclonic 2A (Lafora)

MIM: 254780

Lafora disease (LD) is characterized by fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures, visual hallucinations (occipital seizures), and progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, and ataxia beginning in previously healthy adolescents between ages 12 and 17 years. The frequency and intractability of seizures increase over time. Status epilepticus is common. Emotional disturbance and confusion are common at or soon after onset of seizures and are followed by dementia. Dysarthria and ataxia appear early, spasticity late. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration.

Diagnosis Testing

Diagnosis is usually based on clinical and EEG findings and detection of two mutations in one of the two genes known to be associated with LD: EPM2A or NHLRC1 (EPM2B). On rare occasion skin biopsy to detect pathognomonic Lafora bodies is necessary to confirm the diagnosis.

Genetic Counseling

Lafora disease is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for at-risk pregnancies are possible if the disease-causing mutations in the family are known.

References

PMID: 20301563

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Interactions

Products	Interactant	Other Gene	Source	Pubs	Description
NP_005661.1	NP_055620.1	EPM2AIP1	BIND	PubMed	Laforin interacts with EPM2AIP1.
O95278	Q7L775	EPM2AIP1	HPRD	PubMed
O95278	Q9UMS0	NFU1	HPRD	PubMed
BioGRID:113679	BioGRID:109187	GSK3B	BioGRID	PubMed	Affinity Capture-Western; Two-hybrid
BioGRID:113679	BioGRID:109541	HSPA5	BioGRID	PubMed	Co-localization
BioGRID:113679	BioGRID:118095	NFU1	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex; Two-hybrid
BioGRID:113679	BioGRID:132073	NHLRC1	BioGRID	PubMed	Affinity Capture-Western; Biochemical Activity; Co-localization; Reconstituted Complex; Two-hybrid
BioGRID:113679	BioGRID:111500	PPP1R3C	BioGRID	PubMed	Affinity Capture-Western
BioGRID:113679	BioGRID:111550	PRKAA2	BioGRID	PubMed	Affinity Capture-Western; Biochemical Activity; Two-hybrid
BioGRID:113679	BioGRID:111552	PRKAB2	BioGRID	PubMed	Two-hybrid
BioGRID:113679	BioGRID:113164	UBC	BioGRID	PubMed	Affinity Capture-Western; Co-localization
BioGRID:113679	BioGRID:113169	UBE2D1	BioGRID	PubMed	Co-localization

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General gene information

Markers

SHGC-132306 (e-PCR)
- UniSTS:170771

D10S275 (e-PCR)
- UniSTS:147992

SHGC-83278 (e-PCR)
- UniSTS:101156

SHGC-78150 (e-PCR)
- UniSTS:101192

RH122690 (e-PCR)
- UniSTS:133968

RH103579 (e-PCR)
- UniSTS:97904

SHGC-144778 (e-PCR)
- UniSTS:172413

D6S1443 (e-PCR)
- UniSTS:83138

AL035166 (e-PCR)
- UniSTS:94679

WI-13634 (e-PCR)
- UniSTS:1244

D6S1703 (e-PCR), detects polymorphism
- UniSTS:74211

Genotypes

See EPM2A SNP Geneview Report
See EPM2A SNP Genotype Report
See EPM2A SNP Variation Viewer Report

Homology

Homologs of the EPM2A gene: The EPM2A gene is conserved in chimpanzee, , cow, mouse, chicken, and zebrafish.
Map Viewer (Mouse)

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
carbohydrate binding	IEA Inferred from Electronic Annotation more info
hydrolase activity	IEA Inferred from Electronic Annotation more info
protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein serine/threonine phosphatase activity	IDA Inferred from Direct Assay more info	PubMed
protein serine/threonine phosphatase activity	TAS Traceable Author Statement more info	PubMed
protein tyrosine phosphatase activity	IDA Inferred from Direct Assay more info	PubMed
protein tyrosine phosphatase activity	NAS Non-traceable Author Statement more info	PubMed
protein tyrosine/serine/threonine phosphatase activity	IEA Inferred from Electronic Annotation more info
starch binding	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
carbohydrate metabolic process	IEA Inferred from Electronic Annotation more info
glycogen metabolic process	NAS Non-traceable Author Statement more info	PubMed
peptidyl-tyrosine dephosphorylation	IDA Inferred from Direct Assay more info	PubMed
peptidyl-tyrosine dephosphorylation	NAS Non-traceable Author Statement more info	PubMed
protein dephosphorylation	IDA Inferred from Direct Assay more info	PubMed

Component	Evidence Code	Pubs
cytoplasm	IDA Inferred from Direct Assay more info	PubMed
cytosol	IDA Inferred from Direct Assay more info	PubMed
endoplasmic reticulum	IEA Inferred from Electronic Annotation more info
nucleus	IEA Inferred from Electronic Annotation more info
plasma membrane	IEA Inferred from Electronic Annotation more info
polysome	IDA Inferred from Direct Assay more info	PubMed

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General protein information

Preferred Names: laforin

Names: laforin; LAFPTPase; lafora PTPase; epilepsy, progressive myoclonus type 2, Lafora disease (laforin)

NP_001018051.1

EC 3.1.3.16

EC 3.1.3.48

NP_005661.1

EC 3.1.3.16

EC 3.1.3.48

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NCBI Reference Sequences (RefSeq)

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_012832.1 RefSeqGene

Range

5001..115552

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001018041.1 → NP_001018051.1 laforin isoform b

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks a segment of the coding region compared to variant 1. The resulting isoform (b), also known as C-terISO, contains a shorter and distinct C-terminus compared to isoform a. Isoform b has been localized to the nucleus.

Source sequence(s)

AF284580, AF454491, AF454494, AJ130764, AL023806, AW291546, BC070047, BI463677

UniProtKB/Swiss-Prot

O95278

Related

ENSP00000405913, OTTHUMP00000017361, ENST00000435470, OTTHUMT00000042566

Conserved Domains (2) summary

cl00053
Location:158 – 303
Blast Score: 177

PTPc; Protein tyrosine phosphatases (PTP) catalyze the dephosphorylation of phosphotyrosine peptides; they regulate phosphotyrosine levels in signal transduction pathways. The depth of the active site cleft renders the enzyme specific for phosphorylated Tyr ...

cl15347
Location:19 – 129
Blast Score: 382

CBM20; The family 20 carbohydrate-binding module (CBM20), also known as the starch-binding domain, is found in a large number of starch degrading enzymes including alpha-amylase, beta-amylase, glucoamylase, and CGTase (cyclodextrin glucanotransferase). CBM20 is ...
NM_005670.3 → NP_005661.1 laforin isoform a

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longer transcript, and encodes the longer isoform (a). Isoform a has been localized to the rough endoplasmic reticulum.

Source sequence(s)

AF284580, AF454494, AL023806, AW291546, BC005286

Consensus CDS

CCDS5206.1

UniProtKB/Swiss-Prot

O95278

Related

ENSP00000356489, OTTHUMP00000017360, ENST00000367519, OTTHUMT00000042564

Conserved Domains (2) summary

cl00053
Location:158 – 303
Blast Score: 177

PTPc; Protein tyrosine phosphatases (PTP) catalyze the dephosphorylation of phosphotyrosine peptides; they regulate phosphotyrosine levels in signal transduction pathways. The depth of the active site cleft renders the enzyme specific for phosphorylated Tyr ...

cl15347
Location:19 – 129
Blast Score: 384

CBM20; The family 20 carbohydrate-binding module (CBM20), also known as the starch-binding domain, is found in a large number of starch degrading enzymes including alpha-amylase, beta-amylase, glucoamylase, and CGTase (cyclodextrin glucanotransferase). CBM20 is ...

RefSeqs of Annotated Genomes: Build 37.3

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p5 Primary Assembly

Genomic

NC_000006.11 Reference GRCh37.p5 Primary Assembly

Range

145946440..146056991, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000138.1 Alternate HuRef

Range

143510000..143620189, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

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Related Sequences

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	AL023806.1	CAI21419.1
		CAI21420.1
		CAI21421.1
genomic	AL023806.1	CAI21419.1
		CAI21420.1
		CAI21421.1
genomic	AL031119.1	CAI20057.1
genomic	AL365193.12	CAI21675.1
		CAI21676.1
		CAI21677.1
genomic	AL365193.12	CAI21675.1
		CAI21676.1
		CAI21677.1
genomic	CH471051.2	EAW47842.1
		EAW47843.1
		EAW47844.1
mRNA	AF084535.2	AAC83347.2
mRNA	AF284580.1	AAG18377.1
mRNA	AF454491.1	AAO15523.1
mRNA	AF454492.1	AAO15524.1
mRNA	AF454493.1	AAO15525.1
mRNA	AF454494.1	AAO15526.1
mRNA	AJ130763.1	CAA10199.1
mRNA	AJ130764.1	CAA10200.1
mRNA	AK022721.1	BAG51107.1
mRNA	AK299497.1	BAG61454.1
mRNA	AW291546.1	None
mRNA	BC005286.1	AAH05286.1
mRNA	BC070047.1	AAH70047.1
mRNA	BI463677.1	None