O95278 (EPM2A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Laforin
EC=3.1.3.16
EC=3.1.3.48

Alternative name(s):
Lafora PTPase
Short name=LAFPTPase

Gene names

Name:

EPM2A

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	331 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Dual specificity protein phosphatase. May be involved in the control of glycogen metabolism, particularly in monitoring for and preventing the formation of poorly branched glycogen molecules (polyglucosans). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Forms a complex with NHLRC1/malin and HSP70 and this complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Isoform 2, an inactive phosphatase, could function as a dominant-negative regulator for the phosphatase activity of isoform 1. Ref.1 Ref.2 Ref.10 Ref.19 Ref.20 Ref.21
Catalytic activity	Protein tyrosine phosphate + H2O = protein tyrosine + phosphate. A phosphoprotein + H2O = a protein + phosphate.
Subunit structure	Interacts with itself. Interacts also with PPP1R3C, HIRIP5 and EPM2AIP1. Binds glycogen and Lafora bodies. Interacts with NHLRC1/malin (via the NHL repeats). Forms a complex with NHLRC1/malin and HSP70. Isoform 2 does not bind glycogen. Isoform 1 and isoform 2 interact to form a heterodimeric complex inactive as phosphatase in vitro. Active phosphatase isoform 7 interacts with isoform 1 or isoform 2 to form a heterodimeric complex inactive as phosphatase in vitro. Ref.13 Ref.14 Ref.15 Ref.17 Ref.19 Ref.20
Subcellular location	Cytoplasm Ref.2 Ref.10 Ref.11 Ref.12 Ref.18 Ref.19. Note: Under glycogenolytic conditions localizes to the nucleus. Ref.2 Ref.10 Ref.11 Ref.12 Ref.18 Ref.19 Isoform 1: Endoplasmic reticulum. Cell membrane. Note: Primarily associated with polyribosomes at the endoplasmic reticulum, also found at the plasma membrane. Ref.2 Ref.10 Ref.11 Ref.12 Ref.18 Ref.19 Isoform 2: Endoplasmic reticulum. Cell membrane. Nucleus Ref.2 Ref.10 Ref.11 Ref.12 Ref.18 Ref.19. Note: Also found in the nucleus. Ref.2 Ref.10 Ref.11 Ref.12 Ref.18 Ref.19 Isoform 4: Cytoplasm Ref.2 Ref.10 Ref.11 Ref.12 Ref.18 Ref.19. Nucleus Ref.2 Ref.10 Ref.11 Ref.12 Ref.18 Ref.19. Isoform 5: Cytoplasm Ref.2 Ref.10 Ref.11 Ref.12 Ref.18 Ref.19. Nucleus Ref.2 Ref.10 Ref.11 Ref.12 Ref.18 Ref.19. Isoform 7: Cytoplasm Ref.2 Ref.10 Ref.11 Ref.12 Ref.18 Ref.19.
Tissue specificity	Expressed in heart, skeletal muscle, kidney, pancreas and brain. Isoform 4 is also expressed in the placenta. Ref.1
Post-translational modification	Polyubiquitinated by NHLRC1/malin. Phosphorylation on Ser-25 by AMPK affects the phosphatase activity of the enzyme and its ability to homodimerize and interact with NHLRC1, PPP1R3C or PRKAA2.
Involvement in disease	Epilepsy, progressive myoclonic 2 (EPM2) [MIM:254780]: An autosomal recessive and severe form of adolescent-onset progressive epilepsy. Typically, as seizures increase in frequency, cognitive function declines towards dementia, and affected individuals die usually within 10 years after onset. EPM2 occurs worldwide, but it is particularly common in the mediterranean countries of southern Europe and northern Africa, in southern India and in the Middle East. At the cellular level, it is characterized by accumulation of starch-like polyglucosans called Lafora bodies (LBs) that are most abundant in organs with the highest glucose metabolism: brain, heart, liver and skeletal muscle. Among other conditions involving polyglucosans, EPM2 is unique in that the inclusions are in neuronal dendrites but not axons and the forming polyglucosan fibrils are associated with the endoplasmic reticulum. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.2 Ref.9 Ref.12 Ref.13 Ref.15 Ref.16 Ref.24 Ref.26 Ref.27 Ref.28 Ref.29 Ref.31
Sequence similarities	Belongs to the protein-tyrosine phosphatase family. Contains 1 CBM20 (carbohydrate binding type-20) domain. Contains 1 tyrosine-protein phosphatase domain.
Sequence caution	The sequence BAG51107.1 differs from that shown. Reason: Frameshift at position 223.

Ontologies

Keywords
Biological process	Carbohydrate metabolism Glycogen metabolism
Cellular component	Cell membrane Cytoplasm Endoplasmic reticulum Membrane Nucleus
Coding sequence diversity	Alternative initiation Alternative splicing Polymorphism
Disease	Disease mutation Epilepsy
Molecular function	Hydrolase Protein phosphatase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	behavior Inferred from electronic annotation. Source: Compara glycogen metabolic process Non-traceable author statement Ref.9. Source: UniProtKB nervous system development Inferred from electronic annotation. Source: Compara
Cellular_component	cytosol Inferred from direct assay Ref.14. Source: UniProtKB endoplasmic reticulum Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell polysome Inferred from direct assay Ref.2. Source: UniProtKB
Molecular_function	protein serine/threonine phosphatase activity Inferred from direct assay Ref.14. Source: UniProtKB protein tyrosine phosphatase activity Inferred from direct assay Ref.2Ref.14. Source: UniProtKB protein tyrosine/serine/threonine phosphatase activity Inferred from electronic annotation. Source: InterPro starch binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
PPP1R3C	Q9UQK1	5	EBI-2506661,EBI-2506727

Alternative products

This entry describes 9 isoforms produced by alternative splicing and alternative initiation. [Align] [Select]

Isoform 1 (identifier: O95278-1)

Also known as: A; LDH1; Laf331;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O95278-2)

Also known as: B; C-terISO; Laf317;

The sequence of this isoform differs from the canonical sequence as follows:
     310-320: LARAQEDFFQK → ASQDTFPL
     321-331: Missing.

Note: Produced by alternative splicing.

Isoform 3 (identifier: O95278-3)

The sequence of this isoform differs from the canonical sequence as follows:
     75-100: GAEPGRVDTFWYKFLKREPGGELSWE → LVKIGSAPETRSKIFPRFTIRRRLSR

Note: Produced by alternative splicing. No experimental confirmation available.

Isoform 4 (identifier: O95278-4)

Also known as: Laf152;

The sequence of this isoform differs from the canonical sequence as follows:
     102-199: NGPHHDRCCT...MNFQTEWDIV → IASRRLPPAQ...VPAHSPGDLG
     200-331: Missing.

Note: Produced by alternative splicing.

Isoform 5 (identifier: O95278-5)

Also known as: Laf224;

The sequence of this isoform differs from the canonical sequence as follows:
     160-293: Missing.
     294-331: YFLMAKRPAV...GKVRSSVCSL → PSTDAAPGGV...PHGQEAGCLH

Note: Produced by alternative splicing.

Isoform 6 (identifier: O95278-6)

Also known as: Laf88;

The sequence of this isoform differs from the canonical sequence as follows:
     1-243: Missing.

Note: Produced by alternative initiation at Met-244 of isoform 1. Transcript amplified but protein not detected.

Isoform 7 (identifier: O95278-7)

Also known as: Laf177;

The sequence of this isoform differs from the canonical sequence as follows:
     1-159: MRFRFGVVVP...AGHQAMHYSR → MIFNK

Note: Produced by alternative splicing. Active phosphatase.

Isoform 8 (identifier: O95278-8)

The sequence of this isoform differs from the canonical sequence as follows:
     1-138: Missing.

Note: Produced by alternative splicing. No experimental confirmation available.

Isoform 9 (identifier: B3EWF7-1)

Also known as: POCR;

The sequence of this isoform can be found in the external entry B3EWF7.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

Note: 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.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 331	331	Laforin		PRO_0000094838
Regions
	Domain	1 – 124	124	CBM20
	Domain	243 – 311	69	Tyrosine-protein phosphatase
Amino acid modifications
	Modified residue	25	1	Phosphoserine; by AMPK Ref.22
Natural variations
	Alternative sequence	1 – 243	243	Missing in isoform 6.		VSP_042494
	Alternative sequence	1 – 159	159	MRFRF…MHYSR → MIFNK in isoform 7.		VSP_042495
	Alternative sequence	1 – 138	138	Missing in isoform 8.		VSP_042493
	Alternative sequence	75 – 100	26	GAEPG…ELSWE → LVKIGSAPETRSKIFPRFTI RRRLSR in isoform 3.		VSP_011014
	Alternative sequence	102 – 199	98	NGPHH…EWDIV → IASRRLPPAQSGSSGPHPQP GPRPRAGPAGPGGARPGLFA RVPAHSPGDLG in isoform 4.		VSP_011015
	Alternative sequence	160 – 293	134	Missing in isoform 5.		VSP_042496
	Alternative sequence	200 – 331	132	Missing in isoform 4.		VSP_011016
	Alternative sequence	294 – 331	38	YFLMA…SVCSL → PSTDAAPGGVPAACAAGEGT HRVRALQRWGGPLHRGCLRL APVCDGLESEEGAVFPHGQE AGCLH in isoform 5.		VSP_042497
	Alternative sequence	310 – 320	11	LARAQEDFFQK → ASQDTFPL in isoform 2.		VSP_011017
	Alternative sequence	321 – 331	11	Missing in isoform 2.		VSP_011018
	Natural variant	25	1	S → P in EPM2; atypical form; does not affect glycogen binding. Ref.16 Ref.26		VAR_019465
	Natural variant	28	1	E → K in EPM2; does not affect glycogen binding. Ref.16		VAR_019466
	Natural variant	32	1	W → G in EPM2; affects phosphatase activity; abolishes glycogen binding; reduced binding to Lafora bodies; disrupts the interaction with PPP1R3C; significant protein amount targeted to the nucleus. Ref.12 Ref.15 Ref.16 Ref.26		VAR_019467
	Natural variant	46	1	A → P Does not affect glycogen binding. Ref.16 Ref.25 Ref.30		VAR_019468
	Natural variant	84	1	F → L in EPM2; affects phosphatase activity and glycogen binding; disrupts the interaction with PPP1R3C. Ref.15 Ref.24		VAR_019469
	Natural variant	88	1	F → L in EPM2; does not affect glycogen binding. Ref.16		VAR_019470
	Natural variant	91	1	R → P in EPM2; atypical form; learning difficuties with childhood-onset. Ref.28 Ref.29		VAR_019471
	Natural variant	108	1	R → C in EPM2; loss of phosphatase activity; reduced self-interaction capacity; disrupts the interaction with PPP1R3C. Ref.1 Ref.15 Ref.26		VAR_019472
	Natural variant	114	1	E → D. Ref.1		VAR_019473
	Natural variant	140	1	K → N in EPM2. Ref.31		VAR_046383
	Natural variant	148	1	N → Y in EPM2. Ref.31		VAR_046384
	Natural variant	171	1	R → H in EPM2; results in ubiquitin-positive perinuclear aggregates; may affect proper folding. Ref.2 Ref.9 Ref.26 Ref.29		VAR_019474
	Natural variant	187	1	T → A in EPM2; abolishes interaction with NHLRC1. Ref.27		VAR_019475
	Natural variant	194	1	T → I in EPM2; results in ubiquitin-positive perinuclear aggregates; loss of phosphatase activity; affects glycogen binding; reduced self-interaction capacity; abolishes interaction with NHLRC1, PPP1R3C and PRKAA2; no effect on phosphorylation of protein. Ref.9 Ref.15 Ref.26		VAR_019476
	Natural variant	210	1	E → K in EPM2. Ref.31		VAR_046385
	Natural variant	240	1	G → S in EPM2; very slight loss of phosphatase activity; does not affect glycogen binding; disrupts the interaction with PPP1R3C. Ref.15 Ref.24		VAR_019477
	Natural variant	279	1	G → S in EPM2; results in ubiquitin-positive perinuclear aggregates; loss of phosphatase activity; affects glycogen binding; disrupts the interaction with PPP1R3C. Ref.1 Ref.9 Ref.15 Ref.26 Ref.29		VAR_019478
	Natural variant	293	1	Q → L in EPM2; results in ubiquitin-positive perinuclear aggregates; may affect proper folding; loss of phosphatase activity; affects glycogen binding; disrupts the interaction with PPP1R3C. Ref.1 Ref.2 Ref.15 Ref.26		VAR_019479
	Natural variant	294	1	Y → N in EPM2; results in ubiquitin-positive perinuclear aggregates; loss of phosphatase activity; affects glycogen binding; disrupts the interaction with PPP1R3C. Ref.9 Ref.15 Ref.26		VAR_019480
	Natural variant	301	1	P → L in EPM2; loss of phosphatase activity; affects glycogen binding; disrupts the interaction with PPP1R3C. Ref.15 Ref.24		VAR_019481
	Natural variant	310	1	L → W in EPM2; alters the subcellular localization of isoform 1; does not affect homodimerization of isoform 1 but prevents heterodimerization of isoform 1 and isoform 2. Ref.31		VAR_046386
Experimental info
	Mutagenesis	25	1	S → A: Partial loss of phosphatase activity. Abolishes homodimerization. Abolishes interaction with NHLRC1, PPP1R3C and PRKAA2. Does not affect glycogen binding. Reduces stability of the protein. Ref.22
	Mutagenesis	25	1	S → D: Partial loss of phosphatase activity. Increases interaction with NHLRC1. Does not affect interaction with NHLRC1, PPP1R3C or PRKAA2. Does not affect binding to carbohydrate. Does not affect homodimerization. Ref.22
	Mutagenesis	87	1	K → A: Partial loss of phosphatase activity. Abolishes glycogen binding. Ref.12
	Mutagenesis	168	1	S → A or D: Abolishes interaction with NHLRC1. Ref.22
	Mutagenesis	187	1	T → D: Abolishes interaction with NHLRC1. Ref.22
	Mutagenesis	194	1	T → D: Does not affect interaction with NHLRC1, PPP1R3C or PRKAA2. Ref.22
	Mutagenesis	235	1	D → A: Loss of phosphatase activity. Does not affect glycogen binding. Ref.15
	Mutagenesis	266	1	C → S: Complete loss of phosphatase activity. Does not affect glycogen binding. Does not affect self-interaction. Increases the interaction with PPP1R3C. Ref.12 Ref.15
	Sequence conflict	193	1	Q → K in AAH70047. Ref.8
	Sequence conflict	248	1	A → P in AAO15523. Ref.4
	Sequence conflict	258	1	K → E in BAG61454. Ref.5
	Sequence conflict	294	1	Y → H in BAG61454. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (A) (LDH1) (Laf331) [UniParc]. Last modified May 1, 2000. Version 2. Checksum: DD79F917262AB458	FASTA	331	37,158
	10 20 30 40 50 60 MRFRFGVVVP PAVAGARPEL LVVGSRPELG RWEPRGAVRL RPAGTAAGDG ALALQEPGLW 70 80 90 100 110 120 LGEVELAAEE AAQDGAEPGR VDTFWYKFLK REPGGELSWE GNGPHHDRCC TYNENNLVDG 130 140 150 160 170 180 VYCLPIGHWI EATGHTNEMK HTTDFYFNIA GHQAMHYSRI LPNIWLGSCP RQVEHVTIKL 190 200 210 220 230 240 KHELGITAVM NFQTEWDIVQ NSSGCNRYPE PMTPDTMIKL YREEGLAYIW MPTPDMSTEG 250 260 270 280 290 300 RVQMLPQAVC LLHALLEKGH IVYVHCNAGV GRSTAAVCGW LQYVMGWNLR KVQYFLMAKR 310 320 330 PAVYIDEEAL ARAQEDFFQK FGKVRSSVCS L
	Isoform 2 (B) (C-terISO) (Laf317) [UniParc]. Checksum: 5646A039398AC24D	FASTA	317	35,519
	10 20 30 40 50 60 MRFRFGVVVP PAVAGARPEL LVVGSRPELG RWEPRGAVRL RPAGTAAGDG ALALQEPGLW 70 80 90 100 110 120 LGEVELAAEE AAQDGAEPGR VDTFWYKFLK REPGGELSWE GNGPHHDRCC TYNENNLVDG 130 140 150 160 170 180 VYCLPIGHWI EATGHTNEMK HTTDFYFNIA GHQAMHYSRI LPNIWLGSCP RQVEHVTIKL 190 200 210 220 230 240 KHELGITAVM NFQTEWDIVQ NSSGCNRYPE PMTPDTMIKL YREEGLAYIW MPTPDMSTEG 250 260 270 280 290 300 RVQMLPQAVC LLHALLEKGH IVYVHCNAGV GRSTAAVCGW LQYVMGWNLR KVQYFLMAKR 310 PAVYIDEEAA SQDTFPL
	Isoform 3 [UniParc]. Checksum: 65E7EC44AE20B083	FASTA	331	37,188
	10 20 30 40 50 60 MRFRFGVVVP PAVAGARPEL LVVGSRPELG RWEPRGAVRL RPAGTAAGDG ALALQEPGLW 70 80 90 100 110 120 LGEVELAAEE AAQDLVKIGS APETRSKIFP RFTIRRRLSR GNGPHHDRCC TYNENNLVDG 130 140 150 160 170 180 VYCLPIGHWI EATGHTNEMK HTTDFYFNIA GHQAMHYSRI LPNIWLGSCP RQVEHVTIKL 190 200 210 220 230 240 KHELGITAVM NFQTEWDIVQ NSSGCNRYPE PMTPDTMIKL YREEGLAYIW MPTPDMSTEG 250 260 270 280 290 300 RVQMLPQAVC LLHALLEKGH IVYVHCNAGV GRSTAAVCGW LQYVMGWNLR KVQYFLMAKR 310 320 330 PAVYIDEEAL ARAQEDFFQK FGKVRSSVCS L
	Isoform 4 (Laf152) [UniParc]. Checksum: 60CD9293F2267EC4	FASTA	152	15,804
	10 20 30 40 50 60 MRFRFGVVVP PAVAGARPEL LVVGSRPELG RWEPRGAVRL RPAGTAAGDG ALALQEPGLW 70 80 90 100 110 120 LGEVELAAEE AAQDGAEPGR VDTFWYKFLK REPGGELSWE GIASRRLPPA QSGSSGPHPQ 130 140 150 PGPRPRAGPA GPGGARPGLF ARVPAHSPGD LG
	Isoform 5 (Laf224) [UniParc]. Checksum: 66ECE43870086B2A	FASTA	224	24,134
	10 20 30 40 50 60 MRFRFGVVVP PAVAGARPEL LVVGSRPELG RWEPRGAVRL RPAGTAAGDG ALALQEPGLW 70 80 90 100 110 120 LGEVELAAEE AAQDGAEPGR VDTFWYKFLK REPGGELSWE GNGPHHDRCC TYNENNLVDG 130 140 150 160 170 180 VYCLPIGHWI EATGHTNEMK HTTDFYFNIA GHQAMHYSRP STDAAPGGVP AACAAGEGTH 190 200 210 220 RVRALQRWGG PLHRGCLRLA PVCDGLESEE GAVFPHGQEA GCLH
	Isoform 6 (Laf88) [UniParc]. Checksum: D28FAB18CC285D07	FASTA	88	9,933
	10 20 30 40 50 60 MLPQAVCLLH ALLEKGHIVY VHCNAGVGRS TAAVCGWLQY VMGWNLRKVQ YFLMAKRPAV 70 80 YIDEEALARA QEDFFQKFGK VRSSVCSL
	Isoform 7 (Laf177) [UniParc]. Checksum: 5AE29B26B72E7BF7	FASTA	177	20,256
	10 20 30 40 50 60 MIFNKILPNI WLGSCPRQVE HVTIKLKHEL GITAVMNFQT EWDIVQNSSG CNRYPEPMTP 70 80 90 100 110 120 DTMIKLYREE GLAYIWMPTP DMSTEGRVQM LPQAVCLLHA LLEKGHIVYV HCNAGVGRST 130 140 150 160 170 AAVCGWLQYV MGWNLRKVQY FLMAKRPAVY IDEEALARAQ EDFFQKFGKV RSSVCSL
	Isoform 8 [UniParc]. Checksum: 3DC9436A9885B915	FASTA	193	22,160
	10 20 30 40 50 60 MKHTTDFYFN IAGHQAMHYS RILPNIWLGS CPRQVEHVTI KLKHELGITA VMNFQTEWDI 70 80 90 100 110 120 VQNSSGCNRY PEPMTPDTMI KLYREEGLAY IWMPTPDMST EGRVQMLPQA VCLLHALLEK 130 140 150 160 170 180 GHIVYVHCNA GVGRSTAAVC GWLQYVMGWN LRKVQYFLMA KRPAVYIDEE ALARAQEDFF 190 QKFGKVRSSV CSL
	Isoform 9 (POCR) [UniParc]. See B3EWF7.		–	–

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy." Minassian B.A., Lee J.R., Herbrick J.-A., Huizenga J., Soder S., Mungall A.J., Dunham I., Gardner R., Fong C.G., Carpenter S., Jardim L., Satishchandra P., Andermann E., Snead O.C. III, Lopes-Cendes I., Tsui L.-C., Delgado-Escueta A.V., Rouleau G.A., Scherer S.W. Nat. Genet. 20:171-174(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), ALTERNATIVE SPLICING, PROBABLE FUNCTION, TISSUE SPECIFICITY, VARIANTS EPM2 CYS-108; SER-279 AND LEU-293, VARIANT ASP-114.
[2]	"Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes." Ganesh S., Agarwala K.L., Ueda K., Akagi T., Shoda K., Usui T., Hashikawa T., Osada H., Delgado-Escueta A.V., Yamakawa K. Hum. Mol. Genet. 9:2251-2261(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTIONAL CHARACTERIZATION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS EPM2 HIS-171 AND LEU-293. Tissue: Fetal brain.
[3]	Lee J.R., Scherer S.W. Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]	"Cloning of differentially spliced transcripts of the EPM2A gene." Ganesh S., Yamakawa K. Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8), NUCLEOTIDE SEQUENCE [MRNA] OF 25-331 (ISOFORM 4), NUCLEOTIDE SEQUENCE [MRNA] OF 75-331 (ISOFORM 3). Tissue: Cerebellum and Fetal brain.
[5]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 7 AND 8). Tissue: Fetal brain and Teratocarcinoma.
[6]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 6). Tissue: Hypothalamus and Kidney.
[9]	"A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2)." Serratosa J.M., Gomez-Garre P., Gallardo M.E., Anta B., de Bernabe D.B., Lindhout D., Augustijn P.B., Tassinari C.A., Malafosse R.M., Topcu M., Grid D., Dravet C., Berkovic S.F., de Cordoba S.R. Hum. Mol. Genet. 8:345-352(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 82-331 (ISOFORMS 1 AND 2), VARIANTS EPM2 HIS-171; ILE-194; SER-279 AND ASN-294.
[10]	"Laforin is a cell membrane and endoplasmic reticulum-associated protein tyrosine phosphatase." Minassian B.A., Andrade D.M., Ianzano L., Young E.J., Chan E., Ackerley C.A., Scherer S.W. Ann. Neurol. 49:271-275(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[11]	"Alternative splicing modulates subcellular localization of laforin." Ganesh S., Suzuki T., Yamakawa K. Biochem. Biophys. Res. Commun. 291:1134-1137(2002) [PubMed] [Europe PMC] [Abstract] Cited for: ALTERNATIVE SPLICING, SUBCELLULAR LOCATION (ISOFORM 2).
[12]	"A unique carbohydrate binding domain targets the Lafora disease phosphatase to glycogen." Wang J., Stuckey J.A., Wishart M.J., Dixon J.E. J. Biol. Chem. 277:2377-2380(2002) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOGEN-BINDING, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT EPM2 GLY-32, MUTAGENESIS OF LYS-87 AND CYS-266.
[13]	"Identification of a novel protein interacting with laforin, the EPM2A progressive myoclonus epilepsy gene product." Ianzano L., Zhao X.C., Minassian B.A., Scherer S.W. Genomics 81:579-587(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH EPM2AIP1.
[14]	"The Lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a NifU-like domain." Ganesh S., Tsurutani N., Suzuki T., Ueda K., Agarwala K.L., Osada H., Delgado-Escueta A.V., Yamakawa K. Hum. Mol. Genet. 12:2359-2368(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HIRIP5.
[15]	"Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation." Fernandez-Sanchez M.E., Criado-Garcia O., Heath K.E., Garcia-Fojeda B., Medrano-Fernandez I., Gomez-Garre P., Sanz P., Serratosa J.M., Rodriguez de Cordoba S. Hum. Mol. Genet. 12:3161-3171(2003) [PubMed] [Europe PMC] [Abstract] Cited for: SELF-INTERACTION, INTERACTION WITH PPP1R3C, MUTAGENESIS OF ASP-235 AND CYS-266, CHARACTERIZATION OF VARIANTS EPM2 GLY-32; LEU-84; CYS-108; ILE-194; SER-240; SER-279; LEU-293; ASN-294 AND LEU-301.
[16]	"The carbohydrate-binding domain of Lafora disease protein targets Lafora polyglucosan bodies." Ganesh S., Tsurutani N., Suzuki T., Hoshii Y., Ishihara T., Delgado-Escueta A.V., Yamakawa K. Biochem. Biophys. Res. Commun. 313:1101-1109(2004) [PubMed] [Europe PMC] [Abstract] Cited for: BINDING TO LAFORA BODIES, CHARACTERIZATION OF VARIANTS EPM2 PRO-25; LYS-28; GLY-32 AND LEU-88, CHARACTERIZATION OF VARIANT PRO-46.
[17]	"Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin." Gentry M.S., Worby C.A., Dixon J.E. Proc. Natl. Acad. Sci. U.S.A. 102:8501-8506(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NHLRC1, POLYUBIQUITINATION.
[18]	"A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori's disease." Cheng A., Zhang M., Gentry M.S., Worby C.A., Dixon J.E., Saltiel A.R. Genes Dev. 21:2399-2409(2007) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[19]	"Modulation of functional properties of laforin phosphatase by alternative splicing reveals a novel mechanism for the EPM2A gene in Lafora progressive myoclonus epilepsy." Dubey D., Ganesh S. Hum. Mol. Genet. 17:3010-3020(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, HOMODIMERIZATION, HETERODIMERIZATION, SUBCELLULAR LOCATION.
[20]	"Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG)." Worby C.A., Gentry M.S., Dixon J.E. J. Biol. Chem. 283:4069-4076(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH PPP1R3C.
[21]	"The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system." Garyali P., Siwach P., Singh P.K., Puri R., Mittal S., Sengupta S., Parihar R., Ganesh S. Hum. Mol. Genet. 18:688-700(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, COMPLEX FORMATION WITH NHLRC1 AND HSP70.
[22]	"Laforin, a dual-specificity phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase." Roma-Mateo C., Solaz-Fuster Mdel C., Gimeno-Alcaniz J.V., Dukhande V.V., Donderis J., Worby C.A., Marina A., Criado O., Koller A., Rodriguez De Cordoba S., Gentry M.S., Sanz P. Biochem. J. 439:265-275(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-25 (ISOFORM 1), MUTAGENESIS OF SER-25; SER-168; THR-187 AND THR-194.
[23]	"Identification and characterization of novel splice variants of the human EPM2A gene mutated in Lafora progressive myoclonus epilepsy." Dubey D., Parihar R., Ganesh S. Genomics 99:36-43(2012) [PubMed] [Europe PMC] [Abstract] Cited for: ALTERNATIVE SPLICING (ISOFORMS 4; 5; 6; 7 AND 9).
[24]	"Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions." Gomez-Garre P., Sanz Y., Rodriguez de Cordoba S.R., Serratosa J.M. Eur. J. Hum. Genet. 8:946-954(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS EPM2 LEU-84; SER-240 AND LEU-301.
[25]	"Mutation screening for Japanese Lafora's disease patients: identification of novel sequence variants in the coding and upstream regulatory regions of EPM2A gene." Ganesh S., Shoda K., Amano K., Uchiyama A., Kumada S., Moriyama N., Hirose S., Yamakawa K. Mol. Cell. Probes 15:281-289(2001) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PRO-46.
[26]	"Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype." Ganesh S., Delgado-Escueta A.V., Suzuki T., Francheschetti S., Riggio C., Avanzini G., Rabinowicz A., Bohlega S., Bailey J., Alonso M.E., Rasmussen A., Thomson A.E., Ochoa A., Prado A.J., Medina M.T., Yamakawa K. Hum. Mol. Genet. 11:1263-1271(2002) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS EPM2 PRO-25; CYS-108; HIS-171 AND LEU-293, CHARACTERIZATION OF VARIANTS EPM2 GLY-32; CYS-108; ILE-194; SER-279 AND ASN-294.
[27]	"Two novel mutations in the EPM2A gene in a Korean patient with Lafora's progressive myoclonus epilepsy." Ki C.S., Kong S.Y., Seo D.W., Hong S.B., Kim H.J., Kim J.W. J. Hum. Genet. 48:51-54(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT EPM2 ALA-187.
[28]	"A novel exon 1 mutation in a patient with atypical Lafora progressive myoclonus epilepsy seen as childhood-onset cognitive deficit." Annesi G., Sofia V., Gambardella A., Ciro Candiano I.C., Spadafora P., Annesi F., Cutuli N., De Marco E.V., Civitelli D., Carrideo S., Tarantino P., Barone R., Zappia M., Quattrone A. Epilepsia 45:294-295(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT EPM2 PRO-91.
[29]	"Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy." Ianzano L., Young E.J., Zhao X.C., Chan E.M., Rodriguez M.T., Torrado M.V., Scherer S.W., Minassian B.A. Hum. Mutat. 23:170-176(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS EPM2 PRO-91; HIS-171 AND SER-279.
[30]	"Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population." Singh S., Suzuki T., Uchiyama A., Kumada S., Moriyama N., Hirose S., Takahashi Y., Sugie H., Mizoguchi K., Inoue Y., Kimura K., Sawaishi Y., Yamakawa K., Ganesh S. J. Hum. Genet. 50:347-352(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PRO-46.
[31]	"Lafora disease in the Indian population: EPM2A and NHLRC1 gene mutations and their impact on subcellular localization of laforin and malin." Singh S., Satishchandra P., Shankar S.K., Ganesh S. Hum. Mutat. 29:E1-12(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS EPM2 ASN-140; TYR-148; LYS-210 AND TRP-310, CHARACTERIZATION OF VARIANT EPM2 TRP-310.
+	Additional computationally mapped references.

Web resources

The Lafora progressive myoclonus epilepsy mutation and polymorphism database

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF084535 mRNA. Translation: AAC83347.2. AF284580 mRNA. Translation: AAG18377.1. AF454491 mRNA. Translation: AAO15523.1. AF454492 mRNA. Translation: AAO15524.1. AF454493 mRNA. Translation: AAO15525.1. AF454494 mRNA. Translation: AAO15526.1. AK022721 mRNA. Translation: BAG51107.1. Frameshift. AK299497 mRNA. Translation: BAG61454.1. AL023806, AL365193 Genomic DNA. Translation: CAI21419.1. AL365193, AL023806 Genomic DNA. Translation: CAI21675.1. CH471051 Genomic DNA. Translation: EAW47844.1. BC005286 mRNA. Translation: AAH05286.1. BC070047 mRNA. Translation: AAH70047.1. AJ130763 mRNA. Translation: CAA10199.1. AJ130764 mRNA. Translation: CAA10200.1.
IPI	IPI00423426. IPI00423429. IPI00423430. IPI00423432.
RefSeq	NP_001018051.1. NM_001018041.1. NP_005661.1. NM_005670.3.
UniGene	Hs.486696.
3D structure databases
ProteinModelPortal	O95278.
ModBase	Search...
Protein-protein interaction databases
IntAct	O95278. 2 interactions.
STRING	9606.ENSP00000356489.
Protein family/group databases
CAZy	CBM20. Carbohydrate-Binding Module Family 20.
PTM databases
PhosphoSite	O95278.
Proteomic databases
PaxDb	O95278.
PRIDE	O95278.
Protocols and materials databases
DNASU	7957.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000367519; ENSP00000356489; ENSG00000112425.
GeneID	7957.
KEGG	hsa:7957.
UCSC	uc003qku.3. human. uc003qkv.3. human.
Organism-specific databases
CTD	7957.
GeneCards	GC06M145822.
HGNC	HGNC:3413. EPM2A.
HPA	HPA053643. HPA055468.
MIM	254780. phenotype. 607566. gene.
neXtProt	NX_O95278.
Orphanet	501. Lafora disease.
PharmGKB	PA27832.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG243912.
HOGENOM	HOG000285975.
HOVERGEN	HBG051493.
InParanoid	O95278.
KO	K14165.
OMA	RKVQYFV.
PhylomeDB	O95278.
Gene expression databases
ArrayExpress	O95278.
Bgee	O95278.
CleanEx	HS_EPM2A.
Genevestigator	O95278.
GermOnline	ENSG00000112425. Homo sapiens.
Family and domain databases
Gene3D	2.60.40.10. 1 hit.
InterPro	IPR013784. Carb-bd-like_fold. IPR002044. CBM_fam20. IPR000340. Dual-sp_phosphatase_cat-dom. IPR020422. Dual-sp_phosphatase_subgr_cat. IPR024950. DUSP. IPR013783. Ig-like_fold. IPR000387. Tyr/Dual-sp_Pase. IPR016130. Tyr_Pase_AS. [Graphical view]
PANTHER	PTHR10159. PTHR10159. 1 hit.
Pfam	PF00686. CBM_20. 1 hit. PF00782. DSPc. 1 hit. [Graphical view]
SMART	SM01065. CBM_2. 1 hit. [Graphical view]
SUPFAM	SSF49452. CBD_4. 1 hit.
PROSITE	PS51166. CBM20. 1 hit. PS00383. TYR_PHOSPHATASE_1. 1 hit. PS50056. TYR_PHOSPHATASE_2. 1 hit. PS50054. TYR_PHOSPHATASE_DUAL. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	7957.
NextBio	30475.
SOURCE	Search...

Entry information

Entry name

EPM2A_HUMAN

Accession

Primary (citable) accession number: O95278
Secondary accession number(s): B3KMU5 , B4DRZ2, O95483, Q5T3F5, Q6IS15, Q8IU96, Q8IX24, Q8IX25, Q9BS66, Q9UEN2

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 19, 2004
Last sequence update:	May 1, 2000
Last modified:	May 1, 2013
This is version 113 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.