Disease relevance of NHLRC1

• Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population [1].
• Furthermore, these data distinguish malin as an E3 Ub ligase whose activity is necessary to prevent a neurodegenerative disease that involves formation of nonproteinacious inclusion bodies [2].
• Moreover, we found that six of 17 EPM2B patients preserved daily living activities and social interactions at 4 years from onset, suggesting a slow disease progression [3].
• Progressive myoclonus epilepsies: EPM1, EPM2A, EPM2B [4].

High impact information on NHLRC1

• Mutations in NHLRC1 cause progressive myoclonus epilepsy [5].
• We previously discovered that mutations in EPM2A cause Lafora disease [5].
• For malin-treated platelets were agglutinated by phytohemagglutinin P less extensively and less rapidly than by bovine Factor VIII [6].
• Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation [2].
• A study of gap detection stands at odds with this distinction [Muchnik, C., Efrati, M., Nemeth, E., Malin, M., Hildesheimer, M., 1991. Central auditory skills in blind and sighted subjects. Scand. Audiol. 20(1), 19-23] [7].

Biological context of NHLRC1

• A second gene for LD, termed NHLRC1 and encoding a putative E3 ubiquitin ligase, was recently identified on chromosome 6p22 [1].
• Missense mutations in malin that are present in LD patients abolish its ability to polyubiquitinate and signal the degradation of laforin [2].
• NHLRC1 encodes a protein named malin, containing a zinc finger of the RING type in the N-terminal half and 6 NHL-repeat domains in the C-terminal direction [8].

Anatomical context of NHLRC1

• The disease is caused by mutations of the EPM2A gene, which encodes two isoforms of the laforin protein tyrosine phosphatase, having alternate carboxyl termini, one localized in the cytoplasm (endoplasmic reticulum) and the other in the nucleus [9].

Regulatory relationships of NHLRC1

• Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin [2].

Other interactions of NHLRC1

• To date 43 different variations in EPM2A and 23 in NHLRC1 are known, including missense, nonsense, frameshift, and deletions [8].

Analytical, diagnostic and therapeutic context of NHLRC1

• We identified large EPM2A and EPM2B deletions undetectable by PCR in the heterozygous state and describe simple methods for their routine detection [10].

References