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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 15 days ago
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NHLRC1
NHL repeat containing E3 ubiquitin protein ligase 1
Chromosome 6 Β· 6p22.3
NCBI Gene: 378884Ensembl: ENSG00000187566.6HGNC: HGNC:21576UniProt: Q6VVB1
53PubMed Papers
21Diseases
0Drugs
49Pathogenic Variants
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
ubiquitin-dependent protein catabolic processubiquitin-protein transferase activityprotein bindingubiquitin protein ligase activityLafora diseasemyoclonic epilepsy of Lafora 2myoclonic epilepsy of Lafora 1aging
✦AI Summary

NHLRC1 encodes malin, an E3 ubiquitin ligase that plays a critical role in preventing abnormal glycogen accumulation and protein aggregation. The protein functions in partnership with the phosphatase EPM2A/laforin to regulate glycogen metabolism through multiple degradation pathways 1. NHLRC1 promotes ubiquitin-dependent degradation of glycogen-targeting protein phosphatase subunits and other substrates via the ubiquitin-proteasome system, while also facilitating proteasome-independent degradation through macroautophagy 1. Mutations in NHLRC1 cause Lafora disease, a fatal autosomal recessive progressive myoclonus epilepsy characterized by teenage onset and accumulation of polyglucosan bodies 23. The disease manifests with myoclonus, tonic-clonic seizures, visual hallucinations, and progressive neurological deterioration typically beginning at 12-15 years of age 3. Nearly 100 distinct mutations have been identified in NHLRC1, with missense mutations comprising nearly half of all variants 3. Mutant forms of malin show altered subcellular localization, which may contribute to disease pathogenesis 4. Complete gene deletions have been associated with particularly severe phenotypes 5.

Sources cited
1
NHLRC1 mutations cause polyglucosan storage diseases involving abnormal glycogen metabolism
PMID: 26278982
2
NHLRC1 mutations cause Lafora disease, an autosomal recessive progressive myoclonus epilepsy
PMID: 22047982
3
Lafora disease symptoms include myoclonus, seizures, and neurological deterioration starting at 12-15 years; nearly 100 distinct NHLRC1 mutations identified
PMID: 19267391
4
Mutant malin proteins show altered subcellular localization that may contribute to disease pathogenesis
PMID: 18311786
5
Complete NHLRC1 gene deletion causes severe Lafora disease phenotype
PMID: 23317923
Disease Associationsβ“˜21
Lafora diseaseOpen Targets
0.78Strong
myoclonic epilepsy of Lafora 2Open Targets
0.76Strong
myoclonic epilepsy of Lafora 1Open Targets
0.67Moderate
agingOpen Targets
0.47Moderate
genetic disorderOpen Targets
0.47Moderate
disorder of glycogen metabolismOpen Targets
0.37Weak
myelosuppressionOpen Targets
0.31Weak
Progressive myoclonic epilepsyOpen Targets
0.06Suggestive
early-onset Lafora body diseaseOpen Targets
0.06Suggestive
neurodegenerative syndrome due to cerebral folate transport deficiencyOpen Targets
0.05Suggestive
Generalized epilepsy with febrile seizures-plusOpen Targets
0.05Suggestive
genetic developmental and epileptic encephalopathyOpen Targets
0.05Suggestive
autosomal dominant epilepsy with auditory featuresOpen Targets
0.05Suggestive
early-onset autosomal dominant Alzheimer diseaseOpen Targets
0.05Suggestive
Unverricht-Lundborg diseaseOpen Targets
0.05Suggestive
generalised epilepsyOpen Targets
0.05Suggestive
isolated focal cortical dysplasiaOpen Targets
0.05Suggestive
Unverricht-Lundborg syndromeOpen Targets
0.05Suggestive
Dentatorubral pallidoluysian atrophyOpen Targets
0.05Suggestive
dentatorubral-pallidoluysian atrophyOpen Targets
0.05Suggestive
Myoclonic epilepsy of Lafora 2UniProt
Pathogenic Variants49
NM_198586.3(NHLRC1):c.436G>A (p.Asp146Asn)Pathogenic
Lafora disease|not provided|not specified|Inborn genetic diseases|Myoclonic epilepsy of Lafora 2
β˜…β˜…β˜†β˜†2026β†’ Residue 146
NM_198586.3(NHLRC1):c.468_469del (p.Gly158fs)Pathogenic
Myoclonic epilepsy of Lafora 2|not provided|Lafora disease|Inborn genetic diseases
β˜…β˜…β˜†β˜†2025β†’ Residue 158
NM_198586.3(NHLRC1):c.205C>G (p.Pro69Ala)Pathogenic
Myoclonic epilepsy of Lafora 2|not provided|Lafora disease|NHLRC1-related disorder|Myoclonic epilepsy of Lafora 1
β˜…β˜…β˜†β˜†2025β†’ Residue 69
NM_198586.3(NHLRC1):c.361G>A (p.Gly121Ser)Pathogenic
Lafora disease|Myoclonic epilepsy of Lafora 2
β˜…β˜…β˜†β˜†2025β†’ Residue 121
NM_198586.3(NHLRC1):c.560A>C (p.His187Pro)Pathogenic
Lafora disease|not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 187
NM_198586.3(NHLRC1):c.386C>A (p.Pro129His)Pathogenic
not provided|Lafora disease|Myoclonic epilepsy of Lafora 2
β˜…β˜…β˜†β˜†2024β†’ Residue 129
NM_198586.3(NHLRC1):c.468del (p.Gly158fs)Pathogenic
not provided|Lafora disease
β˜…β˜…β˜†β˜†2023β†’ Residue 158
NM_198586.3(NHLRC1):c.799dup (p.Val267fs)Pathogenic
Lafora disease
β˜…β˜†β˜†β˜†2025β†’ Residue 267
NM_198586.3(NHLRC1):c.488_542del (p.Gln163fs)Likely pathogenic
Myoclonic epilepsy of Lafora 2
β˜…β˜†β˜†β˜†2025β†’ Residue 163
NM_198586.3(NHLRC1):c.137G>A (p.Cys46Tyr)Pathogenic
Lafora disease
β˜…β˜†β˜†β˜†2025β†’ Residue 46
NM_198586.3(NHLRC1):c.1110dup (p.Phe371fs)Pathogenic
Lafora disease
β˜…β˜†β˜†β˜†2025β†’ Residue 371
NM_198586.3(NHLRC1):c.992del (p.Gly331fs)Pathogenic
Myoclonic epilepsy of Lafora 2
β˜…β˜†β˜†β˜†2025β†’ Residue 331
NM_198586.3(NHLRC1):c.940_943dup (p.Tyr315fs)Pathogenic
Lafora disease
β˜…β˜†β˜†β˜†2024β†’ Residue 315
NM_198586.3(NHLRC1):c.98T>C (p.Phe33Ser)Pathogenic
Lafora disease
β˜…β˜†β˜†β˜†2024β†’ Residue 33
NM_198586.3(NHLRC1):c.519del (p.Asp173fs)Pathogenic
Lafora disease
β˜…β˜†β˜†β˜†2024β†’ Residue 173
NM_198586.3(NHLRC1):c.865_880del (p.Gly288_Val289insTer)Pathogenic
Lafora disease
β˜…β˜†β˜†β˜†2024β†’ Residue 288
NM_198586.3(NHLRC1):c.462dup (p.Asp155Ter)Pathogenic
Lafora disease
β˜…β˜†β˜†β˜†2024β†’ Residue 155
NM_198586.3(NHLRC1):c.836T>C (p.Leu279Pro)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 279
NM_198586.3(NHLRC1):c.575A>T (p.Asp192Val)Likely pathogenic
Lafora disease
β˜…β˜†β˜†β˜†2023β†’ Residue 192
NM_198586.3(NHLRC1):c.558_562del (p.His187fs)Pathogenic
Lafora disease
β˜…β˜†β˜†β˜†2023β†’ Residue 187
View on ClinVar β†—
Related Genes
PPP1R3CProtein interaction95%AGLProtein interaction91%CSTBProtein interaction83%PRDM8Protein interaction80%EPM2AProtein interaction76%KCTD7Protein interaction73%
Tissue Expression6 tissues
Heart
100%
Liver
96%
Bone Marrow
91%
Brain
56%
Lung
20%
Ovary
15%
Gene Interaction Network
Click a node to explore
NHLRC1PPP1R3CAGLCSTBPRDM8EPM2AKCTD7
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted Β· UniProt Q6VVB1
View on AlphaFold β†—
Constraintβ“˜
LOEUFβ“˜
1.13LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.70 [0.45–1.13]
RankingsWhere NHLRC1 stands among ~20K protein-coding genes
  • #8,465of 20,598
    Most Researched53
  • #1,359of 5,498
    Most Pathogenic Variants49 Β· top quartile
  • #11,717of 17,882
    Most Constrained (LOEUF)1.13
Genes detectedNHLRC1
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Polyglucosan storage myopathies.
PMID: 26278982
Mol Aspects Med Β· 2015
1.00
2
Multi-omic underpinnings of epigenetic aging and human longevity.
PMID: 37076473
Nat Commun Β· 2023
0.90
3
Four novel and two recurrent NHLRC1 (EPM2B) and EPM2A gene mutations leading to Lafora disease in six Turkish families.
PMID: 22047982
Epilepsy Res Β· 2012
0.80
4
Lafora disease in the Indian population: EPM2A and NHLRC1 gene mutations and their impact on subcellular localization of laforin and malin.
PMID: 18311786
Hum Mutat Β· 2008
0.70
5
Lafora disease: severe phenotype associated with homozygous deletion of the NHLRC1 gene.
PMID: 23317923
J Neurol Sci Β· 2013
0.60