Alternative titles; symbols
HGNC Approved Gene Symbol: SNORD116-1
Cytogenetic location: 15q11.2 Genomic coordinates (GRCh38): 15:25,051,476-25,051,572 (from NCBI)
Small nucleolar RNAs (snoRNAs), such as SNORD116-1, serve as methylation guidance RNAs in the modification of ribosomal RNA and other small nuclear RNAs. Multiple copies of the SNORD116 gene, including SNORD116-1, are located within the introns of a large primary noncoding transcript, SNHG14 (616259), that originates from the Prader-Willi syndrome (PWS; 176270) critical region on human chromosome 15q11.2 (de los Santos et al., 2000; Runte et al., 2001).
De los Santos et al. (2000) identified and characterized a novel imprinted gene, which they designated PWCR1, within the Prader-Willi syndrome (PWS; 176270) critical region on human chromosome 15q11.2 and mouse chromosome 7. Expressed only from the paternal allele, both genes require the imprinting-center regulatory element for expression and are transcribed from the same strand. Both genes do not appear to encode a protein product. High human/mouse sequence similarity (87% identity) is limited to a 99-bp region, called the HMCR (human-mouse conserved region). The HMCR sequence has features of a C/D box small nuclear RNA (snoRNA) and is represented in an abundant small transcript in both species. Located in nucleoli, snoRNAs serve as methylation guidance RNAs in the modification of ribosomal RNA and other small nuclear RNAs. In addition to the nonpolyadenylated small RNAs, larger polyadenylated PWCR1 transcripts were found in most human tissues, whereas expression of any Pwcr1 RNAs was limited to mouse brain. Genomic sequence analysis showed the presence of multiple copies of PWCR1 and Pwcr1 that were organized within local tandem-repeat clusters. On a multispecies Southern blot, hybridization to an HMCR probe encoding the putative snoRNA was limited to mammals. De los Santos et al. (2000) reviewed genes identified in the chromosome 15q11-q13 region that are expressed only from the paternally derived allele.
Runte et al. (2001) reported that a processed antisense transcript of UBE3A (601623) starts at the imprinting center. The SNURF-SNRPN (182279) sense/UBE3A antisense transcription unit (SNHG14; 616259) spans more than 460 kb and contains at least 148 exons, including previously identified SNURF-SNRPN and IPW (601491) exons. It serves as the host for the previously identified HBII-13, HBII-85, and HBII-52 (SNORD115-1; 609837) snoRNAs, as well as for 4 additional snoRNAs (HBII-436, HBII-437, HBII-438A, and HBII-438B). Almost all of those snoRNAs are encoded within introns of this large transcript. Northern blot analysis revealed that most if not all of the snoRNAs are expressed by processing from these introns. The authors proposed that a lack of these snoRNAs may be causally involved in Prader-Willi syndrome.
De los Santos et al. (2000) determined that SNORD116 genes, including SNORD116-1, are intronless.
De los Santos et al. (2000) mapped the SNORD116 gene cluster, which includes SNORD116-1, within the PWS critical region on chromosome 15q11.2. They mapped the mouse ortholog to the conserved syntenic region on mouse chromosome 7.
Runte et al. (2001) determined that the SNHG14 transcription unit contains a tandem repeat cluster of 27 SNORD116 genes, all but 1 of which are intronic.
Powell et al. (2013) stated that the SNORD115 (see 609837) and SNORD116 snoRNAs are processed from 2 distinct long noncoding RNA (lncRNA) host genes, 115HG and 116HG, respectively, that are transcribed as part of the same primary transcript originating from the imprinting control region (see 616259). By RNA FISH of adult mouse brain, Powell et al. (2013) found that 116Hg and 115Hg appeared as overlapping but distinct cloud-like domains in neuronal cell nuclei. These clouds were observed in neurons in several brain regions, but not in nonneuronal cells and not in liver or spleen. Both 116Hg and 115Hg lncRNA clouds increased in diameter during the first week of postnatal life and localized to the paternal decondensed allele of Snrpn-Ube3a. The 116Hg and 115Hg clouds also increased in size during sleep. RNA/DNA FISH of postmortem human brain confirmed that 116HG formed an RNA cloud that localized to the decondensed SNORD116 paternal allele. Chromatin isolation by RNA purification (ChIRP) in adult mouse brain showed that 116Hg interacted with Snord116 DNA and with the transcriptional activator Rbbp5 (600697) in an RNA-dependent manner. ChIRP, followed by gene ontology analysis, revealed that 116Hg associated with 2,403 genes that were enriched for brain expression, protein transport, protein and chromatin modification, and metabolism.
Balanced translocations affecting the paternal copy of 15q11-q13 are a rare cause of PWS or PWS-like features. Wirth et al. (2001) reported a de novo balanced reciprocal translocation, t(X;15)(q28;q12), in a female patient with atypical PWS. The translocation breakpoints in this patient and 2 previously reported patients mapped 70 to 80 kb distal to the SNURF-SNRPN gene (182279) and defined a breakpoint cluster region. The breakpoints disrupted one of several previously unknown 3-prime exons of this gene. RT-PCR experiments demonstrated that sequences distal to the breakpoint, including the C/D box snoRNA gene cluster HBII-85, as well as IPW (601491) and PAR1 (600161), were not expressed in the patient. The authors suggested that lack of expression of these sequences may contribute to the PWS phenotype.
Sahoo et al. (2008) reported a boy with all of 7 major clinical criteria for Prader-Willi syndrome, including neonatal hypotonia, feeding difficulties and failure to thrive during infancy, excessive weight gain after 18 months, hyperphagia, hypogonadism, and global developmental delay; facial features were considered equivocal. Additional minor features included behavioral problems, sleep apnea, skin picking, speech delay, and small hands and feet relative to height. High-resolution chromosome and array comparative genomic hybridization showed an atypical deletion of the paternal chromosome within the snoRNA region at chromosome 15q11.2. The deletion encompassed HBII-438A, all 29 snoRNAs comprising the HBII-85 cluster, and the proximal 23 of the 42 snoRNAs comprising the HBII-52 cluster. The data suggested that paternal deficiency of the HBII-85 cluster may cause key manifestations of the PWS phenotype, although some atypical features suggested that other genes in the region may make lesser phenotypic contributions.
De Smith et al. (2009) reported a 19-year-old male with hyperphagia, severe obesity, mild learning difficulties, and hypogonadism, in whom diagnostic tests for Prader-Willi syndrome had been negative. The authors identified a 187-kb deletion at chromosome 15q11-q13 that encompassed several exons of SNURF-SNRPN, the HBII-85 cluster, and IPW, but did not include the HBII-52 cluster. HBII-85 snoRNAs, as well as HBII-436, HBII-13, HBII-437, and HBII-438A, were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism, and growth failure. These findings provided direct evidence for the role of a particular family of noncoding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth, and reproduction.
In a 23-year-old woman with Prader-Willi syndrome, Bieth et al. (2015) identified a paternally transmitted 118-kb deletion of the SNORD116 gene cluster. SNORD109A and IPW were also deleted in the patient. SNORD116 expression was absent in patient cells, but present in her unaffected father's cells.
Leung et al. (2009) described epigenetically regulated chromatin decondensation at 2 imprinted snoRNA clusters in human and mouse brain. An 8-fold allele-specific decondensation of snoRNA chromatin was developmentally regulated specifically in maturing mouse neurons, correlating with HBII-85 nucleolar accumulation and increased nucleolar size. Allele-specific decondensation of snoRNA chromatin was also detected for the C/D snoRNA clusters near Gtl2 (MEG3; 605636) in maturing mouse neurons. Reciprocal mouse models revealed a genetic and epigenetic requirement of the 35-kb imprinting center at the Snrpn-Ube3a locus for transcriptionally regulated chromatin decondensation. PWS human brain and imprinting center deletion mouse Purkinje neurons showed significantly decreased nucleolar size, demonstrating the essential role of the 15q11-q13 HBII-85 locus in neuronal nucleolar maturation.
Powell et al. (2013) found that half of the genes associated with 116Hg were upregulated in mice heterozygous for a deletion of the Snord116 repeat cluster (Snord116del mice) compared with wildtype. Snord116del mice exhibited increased energy expenditure corresponding to dysregulation of diurnally expressed Mtor (601231) and the circadian genes Clock (601851), Cry1 (601933), and Per2 (603426). Powell et al. (2013) concluded that 116HG regulates diurnal energy expenditure in the brain.
Bieth, E., Eddiry, S., Gaston, V., Lorenzini, F., Buffet, A., Auriol, F. C., Molinas, C., Cailley, D., Rooryck, C., Arveiler, B., Cavaille, J., Salles, J. P., Tauber, M. Highly restricted deletion of the SNORD116 region is implicated in Prader-Willi syndrome. Europ. J. Hum. Genet. 23: 252-255, 2015. [PubMed: 24916642] [Full Text: https://doi.org/10.1038/ejhg.2014.103]
de los Santos, T., Schweizer, J., Rees, C. A., Francke, U. Small evolutionarily conserved RNA, resembling C/D box small nucleolar RNA, is transcribed from PWCR1, a novel imprinted gene in the Prader-Willi deletion region, which is highly expressed in brain. Am. J. Hum. Genet. 67: 1067-1082, 2000. [PubMed: 11007541] [Full Text: https://doi.org/10.1086/303106]
de Smith, A. J., Purmann, C., Walters, R. G., Ellis, R. J., Holder, S. E., Van Haelst, M. M., Brady, A. F., Fairbrother, U. L., Dattani, M., Keogh, J. M., Henning, E., Yeo, G. S. H., O'Rahilly, S., Froguel, P., Farooqi, I. S., Blakemore, A. I. F. A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism. Hum. Molec. Genet. 18: 3257-3265, 2009. [PubMed: 19498035] [Full Text: https://doi.org/10.1093/hmg/ddp263]
Leung, K. N., Vallero, R. O., DuBose, A. J., Resnick, J. L., LaSalle, J. M. Imprinting regulates mammalian snoRNA-encoding chromatin decondensation and neuronal nucleolar size. Hum. Molec. Genet. 18: 4227-4238, 2009. [PubMed: 19656775] [Full Text: https://doi.org/10.1093/hmg/ddp373]
Powell, W. T., Coulson, R. L., Crary, F. K., Wong, S. S., Ach, R. A., Tsang, P., Yamada, N. A., Yasui, D. H., LaSalle, J. M. A Prader-Willi locus lncRNA cloud modulates diurnal genes and energy expenditure. Hum. Molec. Genet. 22: 4318-4328, 2013. [PubMed: 23771028] [Full Text: https://doi.org/10.1093/hmg/ddt281]
Runte, M., Huttenhofer, A., Gross, S., Kiefmann, M., Horsthemke, B., Buiting, K. The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum. Molec. Genet. 10: 2687-2700, 2001. [PubMed: 11726556] [Full Text: https://doi.org/10.1093/hmg/10.23.2687]
Sahoo, T., del Gaudio, D., German, J. R., Shinawi, M., Peters, S. U., Person, R. E., Garnica, A., Cheung, S. W., Beaudet, A. L. Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nature Genet. 40: 719-721, 2008. [PubMed: 18500341] [Full Text: https://doi.org/10.1038/ng.158]
Wirth, J., Back, E., Huttenhofer, A., Nothwang, H.-G., Lich, C., Gross, S., Menzel, C,, Schinzel, A., Kioschis, P., Tommerup, N., Ropers, H.-H., Horsthemke, B., Buiting, K. A translocation breakpoint cluster disrupts the newly defined 3-prime end of the SNURF-SNRPN transcription unit on chromosome 15. Hum. Molec. Genet. 10: 201-210, 2001. [PubMed: 11159938] [Full Text: https://doi.org/10.1093/hmg/10.3.201]