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NUCLEOLAR PROTEIN 3; NOL3

NUCLEOLAR PROTEIN 3; NOL3

Alternative titles; symbolsNOPOther entities represented in this entry:APOPTOSIS REPRESSOR WITH CARD DOMAIN, INCLUDED; ARC, INCLUDEDNUCLEOLAR PROTEIN, 30-KD, INC...

Alternative titles; symbols

  • NOP

Other entities represented in this entry:

  • APOPTOSIS REPRESSOR WITH CARD DOMAIN, INCLUDED; ARC, INCLUDED
  • NUCLEOLAR PROTEIN, 30-KD, INCLUDED; NOP30, INCLUDED
  • MUSCLE-ENRICHED CYTOSOLIC PROTEIN, INCLUDED; MYP, INCLUDED

HGNC Approved Gene Symbol: NOL3

Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:67,170,537-67,175,736 (from NCBI)

▼ Cloning and Expression
By searching an EST database for apoptosis-regulating proteins with homology to the caspase recruitment domain (CARD) of caspase-9 (CASP9; 602234), Koseki et al. (1998) identified a cDNA encoding ARC (apoptosis repressor with CARD). Sequence analysis predicted that the 208-amino acid ARC protein contains an N-terminal CARD and a C-terminal region rich in proline and glutamic acid. Northern blot analysis detected 5.5- and 1.0-kb ARC transcripts in skeletal muscle and heart, but no expression was detected in brain, placenta, lung, liver, kidney, pancreas, and lymphoid/hematopoietic tissues.

To identify proteins involved in RNA processing, Stoss et al. (1999) used a yeast 2-hybrid screen with SRp30c (SFRS9; 601943) as bait on a HeLa library. They isolated a cDNA encoding a protein that they designated NOP30 (nucleolar protein of 30 kD) based on SDS-PAGE analysis. The authors also identified a cDNA encoding a smaller isoform that they termed MYP (muscle-enriched cytosolic protein), which is created by a frameshift and is identical to the ARC protein reported by Koseki et al. (1998). MYP did not interact with SFRS9. Sequence analysis of the 219-amino acid NOP30 protein predicted that it contains a highly acidic N terminus and a basic C terminus enriched with arginines, serines, and prolines and having multiple phosphorylation sites. Northern blot analysis detected 1.8- and 1.3-kb NOP30 transcripts, with highest expression in heart and skeletal muscle and weak expression in other tissues. In contrast, SFRS9 is relatively strongly and ubiquitously expressed as a 1.35-kb transcript. In situ hybridization analysis showed that NOP30 is expressed in the pia mater, a tissue surrounding the brain containing blood vessels lined with smooth muscle cells. Binding analysis indicated that NOP30 binds to itself and that the N and C termini of NOP30 interact with SFRS9 through its RS domain. Confocal microscopy demonstrated that NOP30, through its arginine-rich C terminus, colocalizes with B23 (NPM1; 164040) in the granular component of nucleoli; however, the majority of NOP30 was localized in the fibrillar component. NOP30 and SFRS9 colocalized in the nucleoplasm. In contrast, MYP, with its acidic N terminus, was predominantly localized in the cytoplasm.

▼ Gene Function
Koseki et al. (1998) showed that expression of the ARC cDNA encoding the smaller transcript inhibited apoptosis in a dose-dependent manner when coexpressed with CASP8 (601763) but not when coexpressed with CASP9. ARC also inhibited apoptosis induced by stimulation of CD95/FAS (TNFRSF6; 134637), tumor necrosis factor receptor-1 (TNFR1, or TNFRSF1A; 191190), and TRAMP/death receptor-3 (DR3, or TNFRSF12; 603366). Enzymatic analysis showed that ARC inhibits the enzymatic activity of CASP8. Immunoprecipitation and immunoblot analysis indicated that ARC interacts with CASP2 (600639) and CASP8 through its N-terminal death effector domain but does not interact with CASP1 (147678), CASP3 (600636), or CASP9.

Li et al. (2002) reported that the function of ARC is regulated by casein kinase II (CK2; see 115441). ARC is phosphorylated at thr149 by CK2, and this phosphorylation targets ARC to mitochondria. ARC is able to bind to CASP8 only when it is localized to mitochondria, not to the cytoplasm. These results revealed a mechanism in which a caspase-inhibiting protein requires phosphorylation in order to prevent apoptosis.

Foo et al. (2007) noted that only about one-half of cancers have p53 (TP53; 191170) loss-of-function mutations. They demonstrated that the apoptotic function of wildtype p53 was inactivated by binding to ARC in the nucleus of human cancer cell lines. ARC bound to the p53 tetramerization domain, which inhibited p53 tetramerization and exposed a nuclear export signal in p53, leading to CRM1 (XPO1; 602559)-dependent relocation of p53 to the cytoplasm. Knockdown of endogenous ARC in breast cancer cells resulted in spontaneous tetramerization of endogenous p53, accumulation of p53 in the nucleus, and activation of endogenous p53 target genes. In primary human breast cancers with nuclear ARC, p53 was almost always wildtype. Conversely, nearly all breast cancers with mutant p53 lacked nuclear ARC. Foo et al. (2007) concluded that nuclear ARC is induced in cancer cells and negatively regulates p53.

Zhang and Herman (2008) found that ARC expression was elevated in all cancer cell lines examined. Reduction of ARC expression by small interfering RNA significantly lowered the resistance of HeLa cells to oxidative stress. The majority of ARC was phosphorylated in cancer cell lines, but not in the H9c2 rat cardiomyocyte cell line. In H9c2 cells, the level of Arc protein appeared to be regulated by proteasomal degradation.

▼ Gene Structure
By genomic sequence analysis, Stoss et al. (1999) determined that the NOL3 gene, which encodes NOP30 and MYP and which they called NOP, is composed of 4 exons. The alternative 5-prime splice site that generates the 2 isoforms is located in exon 2.

▼ Mapping
By radiation hybrid analysis, Stoss et al. (1999) mapped the NOL3 gene to chromosome 16q21-q23. The authors noted that deletion of 16q23.1 leads to disorders in musculoskeletal systems.

▼ Molecular Genetics
In 11 affected members of a large Canadian Mennonite family with familial myoclonus-1 (MYOCL1; 614937), Russell et al. (2012) identified a heterozygous mutation in the NOL3 gene (E21Q; 605235.0001). The mutation was found by genomewide linkage analysis followed by massively parallel and Sanger sequencing. The disorder was characterized by adult onset of slowly progressive multifocal cortical myoclonus, as demonstrated by somatosensory evoked potentials. None of the patients had seizures. Direct sequencing of the NOL3 gene in 5 additional kindreds with cortical myoclonus did not reveal any pathogenic mutations.

Macerollo et al. (2014) analyzed the complete coding sequence of NOL3 in 107 myoclonic patients of British origin and found 1 patient with a missense mutation (c.238G-A; A80T). The variant was not found in the 1000 Genomes Project or Exome Variant Server databases. The man exhibited myoclonic jerks affecting the face and both arms beginning in the fourth decade. Since the age of 15, he had been treated with sodium valporate for generalized epilepsy. There was no family history of the disorder, and no family members were available for clinical or genetic analysis. Macerollo et al. (2014) stated that the pathogenicity of the variant remained uncertain. Hamosh (2019) noted that the A80T variant was present in 33 of 154,500 alleles in the gnomAD database, with an allele frequency 0.0002136.

▼ Animal Model
Duchenne muscular dystrophy (DMD; 310200) is an X-linked recessive disorder characterized by progressive muscle weakness and wasting. Dystrophic muscles undergo increased oxidative stress and altered calcium homeostasis, which may contribute to myofiber loss by triggering both necrosis and apoptosis. Abmayr et al. (2004) cloned and characterized murine Arc and studied its expression in normal and dystrophic mouse muscle. Arc expression levels were normal in dystrophic mdx mice, and overexpression of Arc in transgenic mdx mice failed to alleviate the dystrophic pathology in skeletal muscles, suggesting that misregulation of the molecular pathways regulated by Arc does not significantly contribute to myofiber death.

Russell et al. (2012) demonstrated that knockout of Nol3 in mice did not cause neuronal hyperexcitability. Nol3-null mice had no overt motor phenotype and had normal somatosensory evoked potentials similar to wildtype mice.

▼ ALLELIC VARIANTS ( 1 Selected Example):

.0001 MYOCLONUS, FAMILIAL, 1 (1 family)
NOL3, GLU21GLN
In 11 affected members of a large Canadian Mennonite family with adult-onset familial cortical myoclonus (MYOCL1; 614937), Russell et al. (2012) identified a heterozygous 61G-C transversion in the NOL3 gene, resulting in a glu21-to-gln (E21Q) substitution at a highly conserved residue in the N-terminal CARD domain, a motif that mediates protein-protein binding via electrostatic interactions. The mutation segregated with the disorder in this family and was not found in multiple controls or in several large control databases totaling over 10,000 control chromosomes. Expression of the mutation in HEK293 cells yielded 2 NOL3 protein bands, whereas expression of control NOL3 yielded only 1 band, suggesting that the mutation alters posttranslational modification of NOL3. Because the mutation occurs in a protein-protein interaction motif and is predicted to alter the electrostatic surface potential, Russell et al. (2012) postulated that the mutation may alter the binding of NOL3 to its kinase and/or phosphatase, possibly resulting in a gain of function.

Tags: 16q22.1