NHLRC1 Gene (NHL Repeat Containing E3 Ubiquitin Protein Ligase 1)
Genetic and Functional Insights into NHLRC1: Role in Lafora Disease and Glycogen Metabolism
Gene Information Card
| Symbol | NHLRC1 |
|---|---|
| Full Name | NHL Repeat Containing E3 Ubiquitin Protein Ligase 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 6p22.3 |
| NCBI Gene ID | 378884 ncbi.nlm.nih.gov/gene/378884 |
| Ensembl ID | ENSG00000187566 |
| UniProt ID | Q6VVB1 |
| OMIM ID | 608072 |
| HGNC ID | 29573 |
| Aliases | EPM2B, malin, bA204B7.5 |
Description
NHLRC1 (NHL Repeat Containing E3 Ubiquitin Protein Ligase 1) encodes malin, an E3 ubiquitin ligase that interacts with laforin (EPM2A) to regulate glycogen metabolism. Mutations in NHLRC1 cause Lafora progressive myoclonus epilepsy type 2 (EPM2B), an autosomal recessive neurodegenerative disorder characterized by intracellular polyglucosan (Lafora) bodies.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Lafora progressive myoclonus epilepsy type 2 (EPM2B) | Loss-of-function mutations in NHLRC1 impair ubiquitination and degradation of glycogen synthase and other substrates, leading to accumulation of abnormal glycogen (Lafora bodies) in neurons and other tissues. | OMIM #608072; ClinVar; PMID: 14534157 |
| Lafora disease (general) | NHLRC1 mutations account for approximately 20-30% of Lafora disease cases; the gene product malin forms a complex with laforin to regulate glycogen synthesis. | OMIM #254780; PMID: 14534157 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 3.2 nTPM | Low |
| Muscle | 2.1 nTPM | Low |
| Liver | 1.5 nTPM | Low |
| Heart | 1.8 nTPM | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 2.5 nTPM | Neuronal model |
| HEK293 (embryonic kidney) | 1.9 nTPM | Common overexpression system |
| HepG2 (hepatocellular carcinoma) | 1.2 nTPM | Liver model |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.205C>T (p.Arg69*) | Nonsense | ~10% of EPM2B cases | Loss of function; truncation of malin protein |
| c.436G>A (p.Gly146Arg) | Missense | ~5% of EPM2B cases | Loss of function; disrupts NHL repeat domain |
| c.905_906del (p.Leu302Profs*18) | Frameshift | Rare | Loss of function; premature termination |
| c.694C>T (p.Arg232*) | Nonsense | ~8% of EPM2B cases | Loss of function; truncation |
Mutation functional classification
Loss of Function (LOF)
Majority of NHLRC1 mutations are loss-of-function (nonsense, frameshift, missense in NHL repeats), leading to impaired E3 ligase activity and Lafora body accumulation.
Gain of Function (GOF)
No gain-of-function mutations reported in NHLRC1.
Dominant Negative (DN)
No dominant-negative mutations reported; disease is autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Glycogen metabolism (R-HSA-8982491)
• Ubiquitin-mediated proteolysis (KEGG hsa04120)
• Lafora disease pathway (KEGG hsa05030)
Protein Summary
Malin is a 395-amino acid E3 ubiquitin ligase containing an N-terminal zinc finger domain and six NHL repeats. It forms a complex with laforin (EPM2A) to ubiquitinate and target glycogen synthase and other proteins for proteasomal degradation, thereby controlling glycogen synthesis. Loss of malin function leads to accumulation of poorly branched glycogen (Lafora bodies) in the brain, muscle, and other tissues, causing progressive myoclonus epilepsy.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NHLRC1 Knockout HEK293 Cell Line | EDJ-KQ14419 | Human | 378884 | Details Get a Quote |
| NHLRC1 Knockout A-549 Cell Line | EDJ-KQ44622 | Human | 378884 | Details Get a Quote |
| NHLRC1 Knockout HeLa Cell Line | EDJ-KQ44623 | Human | 378884 | Details Get a Quote |
| NHLRC1 Knockout HCT 116 Cell Line | EDJ-KQ76784 | Human | 378884 | Details Get a Quote |
