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NHLRC1
NHL repeat containing E3 ubiquitin protein ligase 1
The NHLRC1 gene provides instructions for the malin protein, which plays a crucial role in the ubiquitin-proteasome system, helping to degrade unwanted proteins and regulate glycogen metabolism. Malin, encoded by the NHLRC1 gene, is essential for maintaining cellular protein quality control and is particularly important for the survival of neurons in the brain.
NHLRC1 is located on the short (p) arm of chromosome 6, at band 6p22.3. Arm ratio per GRCh38 - banding schematic.
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The NHLRC1 gene, also known as EPM2B or MALIN, contains the instructions for producing the malin protein. This protein is involved in the ubiquitin-proteasome system, which acts as a cellular quality control mechanism by tagging and degrading excess or damaged proteins. Malin is widely active throughout the body's cells but is especially vital for the healthy functioning and survival of nerve cells within the brain.
What the gene does
The malin protein, encoded by NHLRC1, functions as an E3 protein-ubiquitin ligase within the ubiquitin-proteasome system. This system is critical for cellular protein quality control, where malin attaches ubiquitin molecules to target proteins, signalling them for degradation. This process ensures the removal of damaged, misfolded, or surplus proteins, helping to maintain cellular health. Malin also interacts with laforin, a protein produced by the EPM2A gene, and this interaction is believed to be important for regulating the complex sugar glycogen. Glycogen is a primary energy storage molecule, and its proper regulation by malin and laforin may prevent its damaging accumulation in tissues not typically suited for storage, such as the nervous system.
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Chromosome location
The NHLRC1 gene is located on chromosome 6 at position 6p22.3. This precise location on the short arm of chromosome 6 helps define its genomic context within the human genome.
Protein structure
The malin protein, with a length of 395 amino acids, features several distinct domains critical for its function. It contains an N-terminal RING-type (Zinc finger) domain spanning amino acids 26-72. Following this, the protein has multiple NHL repeat domains, specifically NHL 1 (amino acids 113-157), NHL 2 (amino acids 161-204), NHL 3 (amino acids 205-245), NHL 4 (amino acids 248-300), NHL 5 (amino acids 301-349), and NHL 6 (amino acids 350-393). These domains collectively facilitate malin's role as an E3 ubiquitin ligase.
Key variants
Variants within the NHLRC1 gene can affect the structure and function of the malin protein. These genetic changes can range from single amino acid substitutions to larger deletions or insertions of genetic material. Such variants may prevent the cell from producing a functional malin protein or lead to the production of a non-functional version, disrupting vital cellular processes.
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.205C>G | p.Pro69Ala | Pathogenic | ★★☆☆ | Myoclonic epilepsy of Lafora 1 |
c.361G>A | p.Gly121Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Lafora disease |
c.386C>A | p.Pro129His | Pathogenic/Likely pathogenic | ★★☆☆ | Lafora disease |
c.436G>A | p.Asp146Asn | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.468_469del | p.Gly158fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.468del | p.Gly158fs | Pathogenic | ★★☆☆ | Lafora disease |
c.560A>C | p.His187Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Lafora disease |
c.1049_1050del | p.Glu350fs | Pathogenic | ★☆☆☆ | not provided |
c.1091C>A | p.Ser364Ter | Pathogenic | ★☆☆☆ | Lafora disease |
c.1110dup | p.Phe371fs | 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 the NHLRC1 gene are primarily associated with Lafora disease. This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two affected copies of the gene (one from each parent) to develop the disorder. Lafora disease is a severe, progressive neurological disorder characterised by intractable epilepsy, myoclonus, and cognitive decline.
Inheritance pattern
Conditions caused by pathogenic NHLRC1 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
The NHLRC1 gene is included in several expert-curated panels within the UK National Health Service (NHS) Genomic Medicine Service's PanelApp. It is covered on the 'Ataxia and cerebellar anomalies - childhood onset', 'Early onset dementia (encompassing fronto-temporal dementia and prion disease)', 'Early onset or syndromic epilepsy', 'Glycogen storage disease', 'Hereditary ataxia', 'Hereditary ataxia, adult onset', 'Likely inborn error of metabolism', 'Neurodegenerative disorders, adult onset', and 'Undiagnosed metabolic disorders' panels, all with a 'green' status, indicating strong evidence for its association with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the NHLRC1 gene?
The NHLRC1 gene provides instructions for making the malin protein, which is an E3 ubiquitin ligase. This protein is crucial for the ubiquitin-proteasome system, a cellular pathway responsible for tagging and degrading unwanted or damaged proteins, thereby maintaining cellular quality control.
How does NHLRC1 relate to Lafora disease?
Variants in the NHLRC1 gene are a known genetic cause of Lafora disease. These variants typically lead to a non-functional malin protein, disrupting its role in protein degradation and glycogen regulation, which results in the neurological symptoms characteristic of the condition.
Is Lafora disease inherited?
Yes, Lafora disease is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic variant in the NHLRC1 gene, one from each parent, to develop the condition.
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
- 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
- Worby CA, Gentry MS, Dixon JE. Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). The Journal of biological chemistry. 2008. PMID: 18070875
- Vilchez D, Ros S, Cifuentes D. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nature neuroscience. 2007. PMID: 17952067
- Singh S, Sethi I, Francheschetti S. Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy. Journal of medical genetics. 2006. PMID: 16950819
- Gómez-Abad C, Gómez-Garre P, Gutiérrez-Delicado E. Lafora disease due to EPM2B mutations: a clinical and genetic study. Neurology. 2005. PMID: 15781812
- Gentry MS, Worby CA, Dixon JE. Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proceedings of the National Academy of Sciences of the United States of America. 2005. PMID: 15930137
- Chan EM, Young EJ, Ianzano L. Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nature genetics. 2003. PMID: 12958597