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EPM2A
EPM2A glucan phosphatase, laforin
EPM2A encodes laforin, a glycogen-regulating protein essential for nervous system health, with variants causing Lafora disease. The EPM2A gene provides instructions for producing laforin, a phosphatase enzyme that helps control glycogen metabolism in cells throughout the body.
EPM2A is located on the long (q) arm of chromosome 6, at band 6q24.3. Arm ratio per GRCh38 - banding schematic.
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EPM2A encodes laforin, a dual-specificity phosphatase with a distinctive carbohydrate-binding module that distinguishes it from other human phosphatases. The protein plays a critical role in preventing abnormal glycogen accumulation in tissues that do not typically store this energy molecule, particularly within the nervous system [PMID:15831493]. Loss of functional laforin results in the formation of insoluble glycogen-protein aggregates known as Lafora bodies, which are the pathological hallmark of Lafora disease.
Whilst laforin is expressed throughout the body, it appears most critical in nerve cells within the brain. The protein works in concert with other cellular regulators to maintain proper glycogen structure and prevent toxic accumulation that can trigger neurodegeneration [PMID:16829534]. Additionally, laforin may act as a tumour suppressor protein. Understanding EPM2A function has provided important insights into the intersection of metabolic regulation and neurological health.
What the gene does
Laforin functions as a glucan phosphatase, removing phosphate groups from glycogen molecules to regulate their structure and solubility. The protein contains both a phosphatase domain and a carbohydrate-binding module, allowing it to directly bind and modify glycogen polymers. This dual functionality enables laforin to recognise and process glycogen molecules that have become aberrantly phosphorylated.
Research suggests that laforin participates in multiple cellular quality-control pathways [PMID:17088211]. The protein interacts closely with malin, an E3 ubiquitin ligase encoded by the NHLRC1 gene, forming a regulatory complex that targets proteins involved in glycogen metabolism for degradation [PMID:16829534]. Through these interactions, laforin helps maintain the balance between glycogen synthesis and breakdown in tissues where glycogen does not normally accumulate [PMID:15831493].
Studies indicate that laforin may also function as a tumour suppressor protein, contributing to the regulation of cell growth and division. The protein appears active in signal transduction networks that control cellular responses to metabolic stress, though the precise mechanisms underlying these functions remain under investigation.
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Chromosome location
EPM2A is located on the long arm of chromosome 6 at position q24.3. This chromosomal region contains multiple genes involved in metabolic regulation and neurological function. The genomic structure of EPM2A and its neighbouring sequences have been well characterised in clinical diagnostic laboratories.
Protein structure
The laforin protein comprises 344 amino acids and displays a distinctive structural organisation. The protein contains multiple disordered regions, including amino acids 1-44 at the N-terminus, amino acids 58-134, amino acids 158-188 in the middle portion, and amino acids 320-344 at the C-terminus. These extensive disordered regions are interspersed with structured domains that mediate the protein's enzymatic activity and carbohydrate-binding properties. The presence of substantial intrinsic disorder likely contributes to laforin's ability to interact with multiple binding partners and participate in diverse cellular regulatory networks.
Key variants
More than 50 pathogenic variants in EPM2A have been identified in individuals with Lafora disease. The variant spectrum includes single nucleotide changes that alter individual amino acids, as well as deletions and insertions that disrupt the reading frame or remove critical functional regions. Most pathogenic variants prevent cells from producing any laforin protein or result in the production of a non-functional form that cannot properly regulate glycogen metabolism.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.108_139del | p.Ala37fs | Pathogenic | ★★☆☆ | Progressive myoclonic epilepsy |
c.118del | p.Arg39_Leu40insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive myoclonic epilepsy |
c.163C>T | p.Gln55Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.166G>T | p.Glu56Ter | Pathogenic | ★★☆☆ | not provided |
c.179G>A | p.Trp60Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Lafora disease |
c.258C>G | p.Tyr86Ter | Pathogenic | ★★☆☆ | Progressive myoclonic epilepsy |
c.269_275del | p.Lys90fs | Pathogenic | ★★☆☆ | not provided |
c.301+1G>T | - | Pathogenic | ★★☆☆ | Progressive myoclonic epilepsy |
c.302-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive myoclonic epilepsy |
c.302-2A>G | - | Pathogenic | ★★☆☆ | Lafora disease |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in EPM2A cause Lafora disease, a severe autosomal recessive progressive myoclonus epilepsy that typically presents in adolescence. Affected individuals experience recurrent seizures, progressive neurological deterioration, and cognitive decline. The condition is characterised by the accumulation of abnormal glycogen-protein aggregates called Lafora bodies in neurons and other tissues, resulting from the loss of laforin's glycogen-regulatory function.
Inheritance pattern
Conditions caused by pathogenic EPM2A variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
EPM2A holds green (high confidence) classification status across multiple NHS Genomic Medicine Service panels, reflecting its well-established clinical validity. The gene appears on panels for early onset or syndromic epilepsy, glycogen storage disease, and likely inborn error of metabolism, consistent with Lafora disease presenting features. EPM2A is also included in panels for adult onset neurodegenerative disorder, hereditary ataxia, and early onset dementia, recognising the progressive neurological decline associated with this condition. This broad panel representation ensures appropriate testing pathways for individuals presenting with various combinations of seizures, ataxia, and cognitive symptoms.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between EPM2A-related and NHLRC1-related Lafora disease?
Both genes encode proteins that work together to regulate glycogen metabolism, and pathogenic variants in either gene cause clinically indistinguishable forms of Lafora disease. The two forms cannot be differentiated based on symptoms alone and require genetic testing to identify which gene is affected.
At what age does Lafora disease typically begin?
Lafora disease most commonly presents during adolescence, typically between ages 10 and 18 years, with seizures often being the first noticeable symptom. However, the age of onset can vary, and earlier or later presentations have been documented.
How is EPM2A inherited?
EPM2A-related Lafora disease follows an autosomal recessive inheritance pattern, meaning an affected individual must inherit pathogenic variants in both copies of the gene. Parents of an affected individual are typically carriers with one working copy and one non-working copy, and usually do not show symptoms.
References
- Garyali P, Siwach P, Singh PK. The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Human molecular genetics. 2009. PMID: 19036738
- Singh S, Ganesh S. Lafora progressive myoclonus epilepsy: a meta-analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes. Human mutation. 2009. PMID: 19267391
- Liu Y, Wang Y, Wu C. Deletions and missense mutations of EPM2A exacerbate unfolded protein response and apoptosis of neuronal cells induced by endoplasm reticulum stress. Human molecular genetics. 2009. PMID: 19403557
- Solaz-Fuster MC, Gimeno-Alcañiz JV, Ros S. Regulation of glycogen synthesis by the laforin-malin complex is modulated by the AMP-activated protein kinase pathway. Human molecular genetics. 2008. PMID: 18029386
- Liu R, Wang L, Chen C. Laforin negatively regulates cell cycle progression through glycogen synthase kinase 3beta-dependent mechanisms. Molecular and cellular biology. 2008. PMID: 18824542
- Vilchez D, Ros S, Cifuentes D. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nature neuroscience. 2007. PMID: 17952067
- Tagliabracci VS, Turnbull J, Wang W. Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2007. PMID: 18040046
- Worby CA, Gentry MS, Dixon JE. Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. The Journal of biological chemistry. 2006. PMID: 16901901
- Girard JM, Lê KH, Lederer F. Molecular characterization of laforin, a dual-specificity protein phosphatase implicated in Lafora disease. Biochimie. 2006. PMID: 17010495
- Chan EM, Ackerley CA, Lohi H. Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy. Human molecular genetics. 2004. PMID: 15102711
- Ganesh S, Agarwala KL, Ueda K. Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes. Human molecular genetics. 2000. PMID: 11001928
- Serratosa JM, Gómez-Garre P, Gallardo ME. A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2). Human molecular genetics. 1999. PMID: 9931343
- Minassian BA, Lee JR, Herbrick JA. Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nature genetics. 1998. PMID: 9771710