NHLRC1

The NHLRC1 gene encodes malin, a single subunit E3 ubiquitin (UBB; MIM 191339) ligase, which contains a RING-HC-type zinc finger and 6 NHL domains and is subclassified as a member of the RING-HCa family (Gentry et al., 2005 [PubMed 15930137]).[supplied by OMIM

NHL repeat containing 1

E3 ubiquitin-protein ligase. Together with the phosphatase EPM2A/laforin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. In complex with EPM2A/laforin and HSP70, suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Ubiquitinates the glycogen-targeting protein phosphatase subunits PPP1R3C/PTG and PPP1R3D in a laforin-dependent manner and targets them for proteasome-dependent degradation, thus decreasing glycogen accumulation. Polyubiquitinates EPM2A/laforin and ubiquitinates AGL and targets them for proteasome-dependent degradation. Also promotes proteasome-independent protein degradation through the macroautophagy pathway.

AutophagyIEA:UniProtKB-KW
Glycogen biosynthetic processTAS:Reactome
Positive regulation of protein ubiquitinationIEA:Ensembl
Proteasome-mediated ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentIDA:UniProtKB
Protein polyubiquitinationManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of gene expressionIEA:Ensembl
Regulation of protein kinase activityIEA:Ensembl
Regulation of protein localization to plasma membraneIEA:Ensembl
Response to endoplasmic reticulum stressIEA:Ensembl

Endoplasmic reticulum
Nucleus
Localizes at the endoplasmic reticulum and, to a lesser extent, in the nucleus.

Epilepsy, progressive myoclonic 2 (EPM2):
A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM2 is an autosomal recessive and severe form of adolescent-onset progressive epilepsy. Typically, as seizures increase in frequency, cognitive function declines towards dementia, and affected individuals die usually within 10 years after onset. EPM2 occurs worldwide, but it is particularly common in the mediterranean countries of southern Europe and northern Africa, in southern India and in the Middle East. At the cellular level, it is characterized by accumulation of starch-like polyglucosans called Lafora bodies (LBs) that are most abundant in organs with the highest glucose metabolism: brain, heart, liver and skeletal muscle. Among other conditions involving polyglucosans, EPM2 is unique in that the inclusions are in neuronal dendrites but not axons and the forming polyglucosan fibrils are associated with the endoplasmic reticulum.