NHLRC1 NHL repeat containing 1 [Homo sapiens] - Gene

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Summary

Official Symbol: NHLRC1provided by HGNC
Official Full Name: NHL repeat containing 1provided by HGNC
Primary source: HGNC:21576
See related: Ensembl:ENSG00000187566; HPRD:06995; MIM:608072; Vega:OTTHUMG00000014315
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: EPM2A; EPM2B; MALIN; bA204B7.2; MGC119262; MGC119264; MGC119265
Summary: The protein encoded by this gene is a single subunit E3 ubiquitin ligase. Laforin is polyubiquitinated by the encoded protein. Defects in this intronless gene lead to an accumulation of laforin and onset of Lafora disease, also known as progressive myoclonic epilepsy type 2 (EPM2).[provided by RefSeq, Mar 2010]

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Genomic context

Location :: 6p22.3

Sequence :: Chromosome: 6; NC_000006.11 (18120718..18122851, complement)

See NHLRC1 in Epigenomics, MapViewer

Chromosome 6 - NC_000006.11 Genomic Context describing neighboring genes

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Genomic regions, transcripts, and products

Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

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Bibliography

GeneRIFs: Gene References Into Functions What's a GeneRIF?

Our results indicate that malin regulates Wnt signaling pathway through the degradation of dishevelled2 and suggest possible deregulation of Wnt signaling in Lafora disease.
Title: Malin regulates Wnt signaling pathway through degradation of dishevelled2.
Mutations in the NHL repeat containing 1 (NHLRC1) gene are described in association with a more benign clinical course and later age of death in an adolescent patient.
Title: Rapidly progressive phenotype of Lafora disease associated with a novel NHLRC1 mutation.
Laforin and malin are defective in Lafora disease (LD), a neurodegenerative disorder associated with epileptic seizures
Title: Malin and laforin are essential components of a protein complex that protects cells from thermal stress.
malin(C46Y), malin(P69A), malin(D146N), and malin(L261P) mutants failed to downregulate the level of R5/PTG, a regulatory subunit of protein phosphatase 1 involved in glycogen synthesis.
Title: Lafora progressive myoclonus epilepsy: NHLRC1 mutations affect glycogen metabolism.
malin negatively regulates neuronatin and its loss of function in Lafora disease results in increased accumulation of neuronatin
Title: Lafora disease ubiquitin ligase malin promotes proteasomal degradation of neuronatin and regulates glycogen synthesis.
Malin is related to TRIM32 at both the phylogenetic and functional level.
Title: Lafora disease E3-ubiquitin ligase malin is related to TRIM32 at both the phylogenetic and functional level.
study described several novel mutations of EPM2A and NHLRC1 and brought additional data to genetic epidemiology of Lafora disease (LD); emphasized the high mutation rate in patients with classical LD as well as the high negativity rate of skin biopsy
Title: Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease.
These results suggest that the modification introduced by the laforin-malin complex could affect the subcellular distribution of AMPK beta subunits.
Title: The laforin-malin complex, involved in Lafora disease, promotes the incorporation of K63-linked ubiquitin chains into AMP-activated protein kinase beta subunits.
the co-chaperone carboxyl terminus of the Hsc70-interacting protein (CHIP) stabilizes malin by modulating the activity of Hsp70.
Title: Co-chaperone CHIP stabilizes aggregate-prone malin, a ubiquitin ligase mutated in Lafora disease.
Results describe a novel homozygous single-nucleotide variant in the NHLRC1 gene in a Malian consanguineous family.
Title: Novel mutation in the NHLRC1 gene in a Malian family with a severe phenotype of Lafora disease.

Submit: New GeneRIF Correction See all (25)

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Phenotypes

Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Epilepsy, progressive myoclonic 2B (Lafora)

MIM: 254780

Lafora disease (LD) is characterized by fragmentary, symmetric, or generalized myoclonus and/or generalized tonic-clonic seizures, visual hallucinations (occipital seizures), and progressive neurologic degeneration including cognitive and/or behavioral deterioration, dysarthria, and ataxia beginning in previously healthy adolescents between ages 12 and 17 years. The frequency and intractability of seizures increase over time. Status epilepticus is common. Emotional disturbance and confusion are common at or soon after onset of seizures and are followed by dementia. Dysarthria and ataxia appear early, spasticity late. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration.

Diagnosis Testing

Diagnosis is usually based on clinical and EEG findings and detection of two mutations in one of the two genes known to be associated with LD: EPM2A or NHLRC1 (EPM2B). On rare occasion skin biopsy to detect pathognomonic Lafora bodies is necessary to confirm the diagnosis.

Genetic Counseling

Lafora disease is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for at-risk pregnancies are possible if the disease-causing mutations in the family are known.

References

PMID: 20301563

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Interactions

Products	Interactant	Other Gene	Source	Pubs	Description
BioGRID:132073	BioGRID:106686	AGL	BioGRID	PubMed	Affinity Capture-Western
BioGRID:132073	BioGRID:108189	DVL2	BioGRID	PubMed	Affinity Capture-Western; Biochemical Activity; Co-localization; Two-hybrid
BioGRID:132073	BioGRID:113679	EPM2A	BioGRID	PubMed	Affinity Capture-Western; Biochemical Activity; Co-localization; Reconstituted Complex; Two-hybrid
BioGRID:132073	BioGRID:109252	GYS1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:132073	BioGRID:109541	HSPA5	BioGRID	PubMed	Co-localization
BioGRID:132073	BioGRID:110890	NNAT	BioGRID	PubMed	Affinity Capture-Western; Two-hybrid
BioGRID:132073	BioGRID:111500	PPP1R3C	BioGRID	PubMed	Biochemical Activity; Two-hybrid
BioGRID:132073	BioGRID:118052	TUBG2	BioGRID	PubMed	Co-localization
BioGRID:132073	BioGRID:113164	UBC	BioGRID	PubMed	Affinity Capture-Western; Co-localization
BioGRID:132073	BioGRID:113169	UBE2D1	BioGRID	PubMed	Co-localization

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General gene information

Markers

NoName (e-PCR)
- UniSTS:482740

NHLRC1__7158 (e-PCR)
- UniSTS:466358

Genotypes

See NHLRC1 SNP Geneview Report
See NHLRC1 SNP Genotype Report
See NHLRC1 SNP Variation Viewer Report

Homology

Map Viewer (Mouse, Rat)

Pathways from BioSystems

Ubiquitin mediated proteolysis, organism-specific biosystem (from KEGG)
Ubiquitin mediated proteolysis, organism-specific biosystemProtein ubiquitination plays an important role in eukaryotic cellular processes. It mainly functions as a signal for 26S proteasome dependent protein degradation. The addition of ubiquitin to protein...
Ubiquitin mediated proteolysis, conserved biosystem (from KEGG)
Ubiquitin mediated proteolysis, conserved biosystemProtein ubiquitination plays an important role in eukaryotic cellular processes. It mainly functions as a signal for 26S proteasome dependent protein degradation. The addition of ubiquitin to protein...

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
ligase activity	IEA Inferred from Electronic Annotation more info
metal ion binding	IEA Inferred from Electronic Annotation more info
protein binding	IPI Inferred from Physical Interaction more info	PubMed
ubiquitin-protein ligase activity	IDA Inferred from Direct Assay more info	PubMed
zinc ion binding	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
positive regulation of protein ubiquitination	IEA Inferred from Electronic Annotation more info
proteasomal ubiquitin-dependent protein catabolic process	IDA Inferred from Direct Assay more info	PubMed
protein polyubiquitination	IDA Inferred from Direct Assay more info	PubMed

Component	Evidence Code	Pubs
endoplasmic reticulum	IEA Inferred from Electronic Annotation more info
nucleus	IDA Inferred from Direct Assay more info	PubMed
perinuclear region of cytoplasm	IEA Inferred from Electronic Annotation more info

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General protein information

Preferred Names: E3 ubiquitin-protein ligase NHLRC1

Names: E3 ubiquitin-protein ligase NHLRC1; NHL repeat-containing protein 1

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NCBI Reference Sequences (RefSeq)

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_016750.1 RefSeqGene

Range

5001..7134

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_198586.2 → NP_940988.2 E3 ubiquitin-protein ligase NHLRC1

Status: REVIEWED

Source sequence(s)

BK001510

Consensus CDS

CCDS4542.1

UniProtKB/Swiss-Prot

Q6VVB1

Related

ENSP00000345464, OTTHUMP00000016074, ENST00000340650, OTTHUMT00000039958

RefSeqs of Annotated Genomes: Build 37.3

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p5 Primary Assembly

Genomic

NC_000006.11 Reference GRCh37.p5 Primary Assembly

Range

18120718..18122851, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000138.1 Alternate HuRef

Range

18065097..18067230, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

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Related Sequences

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	AL589723.7	CAH71232.1
genomic	CH471087.1	EAW55392.1
mRNA	AY324850.1	AAQ19671.1
mRNA	BC103888.1	AAI03889.1
mRNA	BC103889.1	AAI03890.1
mRNA	BC103890.1	AAI03891.1
mRNA	BK001510.1	DAA01954.1