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NHLRC1 gene

NHL repeat containing E3 ubiquitin protein ligase 1
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Normal Function

The NHLRC1 gene provides instructions for making a protein called malin. Although this protein is active in cells throughout the body, it appears to play a critical role in the survival of nerve cells (neurons) in the brain.

Malin is part of the cell machinery that breaks down (degrades) unwanted proteins within cells. The protein tags damaged and excess proteins with a molecule called ubiquitin, which serves as a signal to degrade these proteins. This process, which is known as the ubiquitin-proteasome system, acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the level of proteins involved in several critical cell activities such as the timing of cell division and growth. Malin belongs to a group of proteins in the ubiquitin-proteasome system called E3 protein-ubiquitin ligases.

Malin targets several proteins for degradation, including laforin (which is produced from the EPM2A gene). The interaction between malin and laforin likely plays a critical role in regulating the production of a complex sugar called glycogen. Glycogen is a major source of stored energy in the body. The body stores this sugar in the liver and muscles, breaking it down when it is needed for fuel. Researchers believe that malin and laforin may prevent a potentially damaging buildup of glycogen in tissues that do not normally store this molecule, such as those of the nervous system.

Health Conditions Related to Genetic Changes

Lafora progressive myoclonus epilepsy

More than 45 mutations in the NHLRC1 gene have been identified in people with Lafora progressive myoclonus epilepsy. Many of these mutations change single protein building blocks (amino acids) in the malin protein. Other mutations delete or insert genetic material in the NHLRC1 gene. Almost all mutations in this gene prevent cells from producing any malin or lead to the production of a nonfunctional version of the protein.

The most common NHLRC1 gene mutation replaces the amino acid proline with the amino acid alanine at position 69 in the malin protein (written as Pro69Ala or P69A). This mutation has been found in many affected individuals of Portuguese, Italian, and Spanish heritage. The second most common NHLRC1 gene mutation replaces the amino acid glycine with a premature stop signal in the instructions for making malin (written as Gly158Ter or G158X). This mutation has been seen in affected individuals from several different ethnic groups.

It is unclear how mutations in the NHLRC1 gene lead to the major features of Lafora progressive myoclonus epilepsy. Studies suggest that a loss of malin prevents cells from regulating the production of glycogen. As a result, distinctive clumps called Lafora bodies form within many types of cells. Lafora bodies are made up of an abnormal form of glycogen (called polyglucosan) that cannot be broken down and used for fuel. Instead, polyglucosans build up to form clumps that can damage cells. Neurons appear to be particularly vulnerable to this type of damage. Although Lafora bodies are found in many of the body's tissues, the signs and symptoms of Lafora progressive myoclonus epilepsy are limited to the nervous system.

Researchers are uncertain how a loss of functional malin contributes to the formation of Lafora bodies. However, a lack of this protein ultimately results in the death of neurons, which interferes with the brain's normal functions. The degeneration of neurons likely underlies the seizures, movement abnormalities, intellectual decline, and other neurological problems seen with Lafora progressive myoclonus epilepsy.

More About This Health Condition

Other Names for This Gene

  • bA204B7.2
  • EPM2B
  • MALIN
  • MGC119262
  • MGC119264
  • MGC119265
  • NHL repeat containing 1
  • NHLC1_HUMAN

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

References

  • Chan EM, Young EJ, Ianzano L, Munteanu I, Zhao X, Christopoulos CC, Avanzini G, Elia M, Ackerley CA, Jovic NJ, Bohlega S, Andermann E, Rouleau GA, Delgado-Escueta AV, Minassian BA, Scherer SW. Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet. 2003 Oct;35(2):125-7. Epub 2003 Sep 7. Citation on PubMed
  • Garyali P, Siwach P, Singh PK, Puri R, Mittal S, Sengupta S, Parihar R, Ganesh S. The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet. 2009 Feb 15;18(4):688-700. doi: 10.1093/hmg/ddn398. Epub 2008 Nov 25. Citation on PubMed
  • Gentry MS, Worby CA, Dixon JE. Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8501-6. Epub 2005 Jun 1. Citation on PubMed or Free article on PubMed Central
  • Gómez-Abad C, Gómez-Garre P, Gutiérrez-Delicado E, Saygi S, Michelucci R, Tassinari CA, Rodríguez de Córdoba S, Serratosa JM. Lafora disease due to EPM2B mutations: a clinical and genetic study. Neurology. 2005 Mar 22;64(6):982-6. Citation on PubMed
  • 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. Hum Mutat. 2009 May;30(5):715-23. doi: 10.1002/humu.20954. Review. Citation on PubMed
  • Singh S, Sethi I, Francheschetti S, Riggio C, Avanzini G, Yamakawa K, Delgado-Escueta AV, Ganesh S. Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy. J Med Genet. 2006 Sep;43(9):e48. Citation on PubMed or Free article on PubMed Central
  • Solaz-Fuster MC, Gimeno-Alcañiz JV, Ros S, Fernandez-Sanchez ME, Garcia-Fojeda B, Criado Garcia O, Vilchez D, Dominguez J, Garcia-Rocha M, Sanchez-Piris M, Aguado C, Knecht E, Serratosa J, Guinovart JJ, Sanz P, Rodriguez de Córdoba S. Regulation of glycogen synthesis by the laforin-malin complex is modulated by the AMP-activated protein kinase pathway. Hum Mol Genet. 2008 Mar 1;17(5):667-78. Epub 2007 Nov 20. Citation on PubMed
  • Vilchez D, Ros S, Cifuentes D, Pujadas L, Vallès J, García-Fojeda B, Criado-García O, Fernández-Sánchez E, Medraño-Fernández I, Domínguez J, García-Rocha M, Soriano E, Rodríguez de Córdoba S, Guinovart JJ. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci. 2007 Nov;10(11):1407-13. Epub 2007 Oct 21. Citation on PubMed
  • Worby CA, Gentry MS, Dixon JE. Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J Biol Chem. 2008 Feb 15;283(7):4069-76. Epub 2007 Dec 10. Citation on PubMed or Free article on PubMed Central
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