Alternative titles; symbols
HGNC Approved Gene Symbol: NOP56
SNOMEDCT: 711158005;
Cytogenetic location: 20p13 Genomic coordinates (GRCh38) : 20:2,652,632-2,658,393 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p13 | Spinocerebellar ataxia 36 | 614153 | Autosomal dominant | 3 |
NOP56 is a component of the box C/D small nucleolar ribonucleoprotein complexes that direct 2-prime-O-methylation of pre-ribosomal RNA (rRNA) during its maturation. NOP56 is predicted to function in an early to middle step in pre-rRNA processing (Hayano et al., 2003).
By searching a human EST database for sequences similar to yeast Nop56, followed by screening a HeLa cell cDNA library, Gautier et al. (1997) cloned NOP56. The deduced 602-amino acid protein is 52% identical to yeast Nop56.
Using RT-PCR, Kobayashi et al. (2011) detected variable Nop56 expression in all mouse tissues examined, with highest expression in spleen, whole brain, cerebral cortex, and cerebellum, and lowest expression in spinal cord, heart, and lung. Immunohistochemical analysis of adult brain detected Nop56 in Purkinje cells of the cerebellum, motor neurons of the hypoglossal nucleus, and spinal cord anterior horn. Western blot analysis detected Nop56 at an apparent molecular mass of 66 kD in both nuclear and cytoplasmic fractions of mouse cerebellum and cerebrum.
Gautier et al. (1997) found that a temperature-sensitive lethal yeast Nop56 mutant inhibited many steps in pre-rRNA processing and led to defects in 60S subunit assembly. Expression of human NOP56 did not complement the Nop56 null mutation.
Using epitope-tagged human NOP56, Hayano et al. (2003) purified NOP56-associated complexes from 293EBNA human kidney cells. Mass spectrometric analyses revealed 62 ribosomal proteins, 45 nonribosomal proteins, and both pre-rRNA and mature rRNA species, suggesting that NOP56 is involved in rRNA processing. Treacle (TCOF1; 606847) was among the proteins associated with NOP56, and association of treacle with NOP56 remained following RNase treatment. Protein pull-down experiments confirmed direct interaction between NOP56 and treacle.
Kobayashi et al. (2011) identified MIR1292 (614155) within intron 1 of the NOP56 gene.
By genomic sequence analysis, Kobayashi et al. (2011) mapped the NOP56 gene to chromosome 20p13.
By genomewide linkage analysis followed by candidate gene sequencing and repeat analysis of 5 Japanese families with spinocerebellar ataxia-36 (SCA36; 614153), Kobayashi et al. (2011) identified a pathogenic heterozygous 6-bp repeat expansion (GGCCTG; rs68063608) in intron 1 of the NOP56 gene (614154.0001). Four additional patients with SCA carrying this repeat expansion were also identified. Overall, 9 (3.6%) unrelated cases were found among 251 cohort patients. Fluorescence in situ hybridization of patient lymphoblastoid cells showed RNA foci, which were not found in control cells, and double staining and gel-shift assays showed that the expanded GGCCUG repeat bound and sequestered the RNA-binding protein SFRS2 (600813), whereas (CUG)(6) did not. In addition, transcription of MIR1292 was significantly decreased in lymphoblastoid cells of SCA patients. The findings indicated that SCA36 is caused by hexanucleotide repeat expansions through a toxic gain of function. The phenotype was characterized by adult-onset cerebellar ataxia with development of motor neuron disease mainly affecting the proximal muscles after long disease duration.
Garcia-Murias et al. (2012) detected an expanded GGCCTG repeat in intron 1 of the NOP56 gene in affected members of 2 large SCA kindreds from the Costa da Morte region in Galicia, Spain and in 8 additional probands with SCA from the same geographic region.
In affected members of 5 families from western Japan with spinocerebellar ataxia-36 (SCA36; 614153), Kobayashi et al. (2011) identified a pathogenic heterozygous 6-bp repeat expansion (GGCCTG; rs68063608) in intron 1 of the NOP56 gene. The repeat expansion segregated with the disease in all pedigrees, and the maximum repeat size in 9 unaffected individuals was 8. Analysis of the expansion revealed approximately 1,500 to 2,500 repeats in 17 cases. Four additional patients with SCA carrying this repeat expansion were identified. Overall, 9 (3.6%) unrelated cases were found among 251 cohort patients; haplotype analysis indicated a founder effect. There was no negative association between age of onset and number of repeats and no obvious anticipation in the pedigrees. Fluorescence in situ hybridization of patient lymphoblastoid cells showed the presence of RNA foci, and double staining and gel-shift assays showed that the expanded GGCCUG repeat bound the RNA-binding protein SFRS2 (600813), whereas (CUG)(6) did not. In addition, transcription of MIR1292 was significantly decreased in lymphoblastoid cells of SCA patients. The findings indicated that SCA36 is caused by hexanucleotide repeat expansions through a toxic gain of function. The phenotype was characterized by adult onset cerebellar ataxia with development of motor neuron disease mainly affecting the proximal muscles after long disease duration.
By linkage analysis followed by detailed examination of the candidate region on 20p in 2 large kindreds from Northern Spain with SCA, Garcia-Murias et al. (2012) identified a pathogenic expanded GGCCTG repeat in intron 1 of the NOP56 gene. A similar pattern was then observed in 8 additional probands with SCA from the same geographic region. Expanded alleles contained 650 to 2,500 repeats, and there was some evidence for genetic anticipation. Normal alleles contained 5 to 14 hexanucleotide repeats. Haplotype analysis indicated a founder effect, and the mutation was estimated to have occurred about 1,275 years ago. SCA36 was the most common form of SCA in this region, accounting for 10 (6.3%) of 160 Galician families.
Garcia-Murias, M., Quintans, B., Arias, M., Seixas, A. I., Cacheiro, P., Tarrio, R., Pardo, J., Millan, M. J., Arias-Rivas, S., Blanco-Arias, P., Dapena, D., Moreira, R., Rodriguez-Trelles, F., Sequeiros, J., Carracedo, A., Silveira, I., Sobrido, M. J. 'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization. Brain 135: 1423-1435, 2012. [PubMed: 22492559] [Full Text: https://doi.org/10.1093/brain/aws069]
Gautier, T., Berges, T., Tollervey, D., Hurt, E. Nucleolar KKE/D repeat proteins Nop56p and Nop58p interact with Nop1p and are required for ribosome biogenesis. Molec. Cell. Biol. 17: 7088-7098, 1997. [PubMed: 9372940] [Full Text: https://doi.org/10.1128/MCB.17.12.7088]
Hayano, T., Yanagida, M., Yamauchi, Y., Shinkawa, T., Isobe, T., Takahashi, N. Proteomic analysis of human Nop56p-associated pre-ribosomal ribonucleoprotein complexes: possible link between Nop56p and the nucleolar protein treacle responsible for Treacher Collins syndrome. J. Biol. Chem. 278: 34309-34319, 2003. [PubMed: 12777385] [Full Text: https://doi.org/10.1074/jbc.M304304200]
Kobayashi, H., Abe, K., Matsuura, T., Ikeda, Y., Hitomi, T., Akechi, Y., Habu, T., Liu, W., Okuda, H., Koizumi, A. Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. Am. J. Hum. Genet. 89: 121-130, 2011. [PubMed: 21683323] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.015]