* 182279

SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE N; SNRPN


Alternative titles; symbols

SMN


Other entities represented in this entry:

SNRPN UPSTREAM READING FRAME, INCLUDED; SNURF, INCLUDED

HGNC Approved Gene Symbol: SNRPN

Cytogenetic location: 15q11.2     Genomic coordinates (GRCh38): 15:24,823,637-24,978,723 (from NCBI)


TEXT

Description

SNRPN, or SNURF-SNRPN, is a bicistronic imprinted gene that encodes 2 polypeptides, the SmN splicing factor, which is involved in RNA processing, and the SNRPN upstream reading frame (SNURF) polypeptide. The SNRPN gene is transcribed exclusively from the paternally inherited chromosome and shows highest expression in brain and heart. SNRPN is located within an imprinted gene cluster in chromosome 15 that is associated with Prader-Willi syndrome (PWS; 176270) and Angelman syndrome (AS; 105830), 2 clinically distinct neurogenetic disorders. PWS arises from loss of function of genes in this region expressed exclusively from the paternal chromosome, suggesting that SNRPN may play a role in its etiology (Rodriguez-Jato et al., 2005).


Cloning and Expression

Small nuclear ribonucleoprotein particles (snRNP) found in spliceosomes contain small RNAs U1 (180680), U2 (180690), U4, U5 (180691), and U6 (180692), and associated polypeptides. Some of these polypeptides are present in all 5 of these snRNPs and others are unique to U1 or U2 snRNPs or have tissue-limited expression patterns. SnRNP-associated proteins have epitopes that react with autoimmune sera. With such an antiserum (Sm), a protein termed SmN was identified and the gene subsequently cloned (McAllister et al., 1988; Li et al., 1989; Schmauss et al., 1989). Although the sequence of SmN shows it to be highly homologous to the ubiquitous core snRNP protein B and its alternatively spliced form B-prime, Ozcelik et al. (1992) noted that SmN is expressed predominantly in brain and especially in central neurons. They suggested that SmN may be involved in brain-specific mRNA splicing.

SNRPN Upstream Reading Frame (SNURF)

Sun et al. (1996) reported a patient with PWS phenotype and a balanced reciprocal translocation t(15;19)(q12;q13.41) of paternal origin in which the breakpoint occurred between exons 0 and 1 of the SNRPN locus, outside of the SmN open reading frame. Based on their findings, Sun et al. (1996) suggested that the 3 upstream exons (exons -1, 0, and 1) of SNRPN encode an additional independent reading frame, SNURF (SNRPN upstream reading frame).

Polycistronic transcripts are common in prokaryotes but rare in eukaryotes. Gray et al. (1999) found that 5 eutherian mammals (cow, rat, mouse, rabbit, and human) have the highly conserved SNURF coding sequence. The vast majority of nucleotide substitutions in SNURF were found to be in the wobble codon position, providing strong evolutionary evidence for selection for protein-coding function. Because SNURF-SNRPN maps to human chromosome 15q11-q13 and is paternally expressed, each cistron is a candidate for a role in the imprinted PWS and PWS mouse models. SNURF encodes a highly basic 71-amino acid protein that is nuclear-localized (as is the product of the SNRPN gene). Because SNURF is the only protein-coding sequence within the imprinting regulatory region in 15q11-q13, it may have provided the original selection for imprinting in this domain. Whereas some human tissues express a minor SNURF-only transcript, mouse tissues express only the bicistronic Snurf-Snrpn transcript. Gray et al. (1999) showed that both SNURF and SNRPN are translated in normal, but not PWS, human and mouse tissues and cell lines. These findings identified SNURF as a protein that is produced along with SNRPN from a bicistronic transcript; polycistronic mRNAs, therefore, are encoded in mammalian genomes where they may form functional operons.

By database analysis, Wawrzik et al. (2009) identified several novel transcripts from the SNURF-SNRPN region, 1 of which included exon 23 from the upstream PWRN1 gene (611215). Exon connection PCR analysis of fetal brain and testis detected 4 transcripts, including 2 that showed splicing between a 3-prime PWRN1 exon and SNURF-SNRPN exons. Wawrzik et al. (2009) suggested that PWNR1 is not an independent gene, but an alternative 5-prime part of SNURF-SNRPN. They also identified a transcript of unknown identity from this region, represented in GenBank as BC035402, that was upregulated in testis at meiosis.

UBE3A Antisense Transcript

Runte et al. (2001) reported that a long processed antisense transcript of UBE3A (601623) starts at the imprinting center (IC) at the 5-prime end of the SNURF-SNRPN gene. For further information on this antisense transcript, see SNHG14 (616259).


Gene Structure

Runte et al. (2001) determined that the SNURF-SNRPN core gene has 10 exons. Exons 1 through 3 encode SNURF, and exons 4 through 10 encode SNRPN. Upstream exon U5 includes the AS-IC element, whereas exon 1 includes the PWS-IC element.

For further information on the transcriptional unit that includes SNURF-SNRPN, see SNHG14 (616259).


Mapping

By study of somatic cell hybrids and hybrid cell lines, Ozcelik et al. (1992) mapped the SNRPN gene to chromosome 15q12 and a processed pseudogene, SNRPNP1, to chromosome 6pter-p21. Furthermore, they showed that SNRPN maps to the minimal deletion interval that is critical for Prader-Willi syndrome.

Mutirangura et al. (1993) constructed a complete YAC contig of the Prader-Willi/Angelman syndrome chromosome region and localized the SNRPN gene to specific YACs within the contig.

Leff et al. (1992) showed that the mouse Snrpn gene maps to chromosome 7 in a region of homology with human chromosome 15q11-q13.


Gene Function

Imprinting of SNRPN

Leff et al. (1992) demonstrated that the Snrpn gene is maternally imprinted in the mouse, suggesting that loss of the paternally derived SNRPN allele may be involved in the PWS phenotype. Cattanach et al. (1992) reported observations indicating that maternal duplication of the central part of mouse chromosome 7, where the Snrpn gene is located, causes an imprinting effect that may correspond to PWS. Paternal duplication was not associated with any detectable effect that might correspond with Angelman syndrome.

Glenn et al. (1993) demonstrated functional imprinting of the human SNRPN gene using RT-PCR. No expression was observed in cultured skin fibroblasts of patients with Prader-Willi syndrome but was found in all patients with Angelman syndrome and in normal controls. Glenn et al. (1993) also demonstrated a parent-specific DNA methylation imprint within intron 5 of the SNRPN gene, which suggested an epigenetic mechanism by which parent-specific expression of this gene might be inherited. Thus, the authors found that the pattern of imprinting fulfills 1 major criterion for SNRPN being involved in pathogenesis of PWS.

Reed and Leff (1994) characterized a sequence polymorphism within expressed portions of the human SNRPN gene and showed that the SNRPN gene is monoallelically expressed in fetal brain and heart and in adult brain. Analysis of maternal DNA and of SNRPN cDNA confirmed that the maternal allele is not expressed in fetal brain and heart. Thus, maternal imprinting of SNRPN supports the hypothesis that paternal absence of SNRPN is responsible for the PWS phenotype.

To examine the chromatin basis of imprinting in the 15q11-q13 region, Saitoh and Wada (2000) investigated the status of histone acetylation of the SNURF-SNRPN locus, which is a key imprinted gene in PWS. Chromatin immunoprecipitation studies showed that the unmethylated CpG island of the active, paternally derived allele associated with acetylated histones, whereas the methylated maternally derived, inactive allele was specifically hypoacetylated. The body of the SNURF-SNRPN gene was associated with acetylated histones on both alleles. Treatment of PWS cells with the DNA methyltransferase inhibitor 5-azadeoxycytidine induced demethylation of the SNURF-SNRPN CpG island and restored gene expression on the maternal allele. The reactivation was associated with increased H4 acetylation but not with H3 acetylation at the SNURF-SNRPN CpG island. These findings indicated that (1) a significant role for histone deacetylation in gene silencing is associated with imprinting in 15q11-q13, and (2) silenced genes in PWS can be reactivated by drug treatment. Thus, the potential for pharmaceutical treatment of imprinting-related disorders was raised.

Using Zfp57 (612192) mutant mice, Li et al. (2008) found that Zfp57 was required for maternal imprinting at the Snrpn locus in the female germline.

SNRPN-Associated Imprinting Center

Dittrich et al. (1996) reported the existence of an imprinting center, which maps to a 100-kb region of chromosome 15q11-q13. This imprinting center encodes alternative transcripts of the SNRPN gene. The novel exons lack protein coding potential and are expressed from the paternal chromosome only. They also reported that families with imprinting mutations have mutations in this transcription unit. Deletions and point mutations of the alternative 5-prime exons of SNRPN (referred to as BD transcripts) are associated with a block of the maternal-paternal imprint switch in several families with Angelman syndrome. Deletions of SNRPN exon 1 are associated with a block of the maternal-paternal imprint switch in several families with Prader-Willi syndrome. Based on their studies, Dittrich et al. (1996) proposed a model for imprint switching. In this model the imprint center consists of an imprinter and an imprint switch initiation site. The imprinter encodes the BD transcript. They proposed that the imprinter is transcribed from the paternal chromosome only and that it acts in cis on the switch initiation site (the SNRPN promoter, exon 1, or a site close by), possibly by introducing a change in chromatin structure.

Prader-Willi syndrome and Angelman syndrome are neurogenetic disorders caused by the lack of a paternal or a maternal contribution from human 15q11-q13, respectively. They involve oppositely imprinted genes: the paternally expressed PWS gene(s) and the maternally expressed AS gene. Deletions in the transcription unit of the imprinted SNRPN gene occur in patients who have PWS or Angelman syndrome because of a parental imprint switch failure in this chromosomal domain. It has been suggested that the SNRPN exon 1 region, which is deleted in PWS patients, contains an imprint switch element from which the maternal and paternal epigenotypes of the 15q11-q13 domain originate. Using the model organism Drosophila, Lyko et al. (1998) showed that a fragment from this region can function as a silencer in transgenic flies. Repression was detected specifically from this element and could not be observed with control human sequences. Additional experiments allowed the delineation of the silencer to a fragment of 215 bp containing the SNRPN promoter region. These results provide an additional link between genomic imprinting and an evolutionarily conserved silencing mechanism. Lyko et al. (1998) suggested that the identified element participates in the long-range regulation of the imprinted 15q11-q13 domain or locally represses SNRPN expression from the maternal allele.

Schweizer et al. (1999) studied the mechanism by which small microdeletions within the 5-prime region of the SNRPN transcription unit affect the transcriptional activity and methylation status of distant imprinted genes throughout 15q11-q13 in cis. They analyzed the chromatin structure of the 150-kb SNRPN transcription unit for DNaseI- and MspI-hypersensitive sites. Using an in vivo approach on lymphoblastoid cell lines from PWS and AS individuals, they discovered that exon 1 of the SNRPN gene is flanked by prominent hypersensitive sites on the paternal allele, but is completely inaccessible to nucleases on the maternal allele. In contrast, they identified several regions of increased nuclease hypersensitivity on the maternal allele, one of which coincides with the minimal microdeletion region for AS, and another that lies in intron 1 immediately downstream of the paternal-specific hypersensitive sites. At several sites, parental origin-specific nuclease hypersensitivity was found to be correlated with hypermethylation on the allele contributed by the other parent. Schweizer et al. (1999) suggested that the differential parental origin-dependent chromatin conformations may govern access of regulatory protein complexes and/or RNAs that mediate interaction of the region with other genes.

Several observations had suggested that cis elements within the AS-SRO (shortest region of overlap) and PWS-SRO constitute an imprinting box that regulates the entire domain on both chromosomes. Shemer et al. (2000) showed that a minitransgene composed of 200-bp Snrpn promoter/exon 1 and a 1-kb sequence located approximately 35 kb upstream to the SNRPN promoter confer imprinting as judged by differential methylation, parent-of-origin-specific transcription, and asynchronous replication.

Geuns et al. (2003) studied the methylation patterns of the imprint control region of the SNRPN gene in human spermatozoa, oocytes at the germinal vesicle, metaphase I, and metaphase II stages, and preimplantation embryos. In spermatozoa, almost all potential methylation sites were unmethylated, whereas near-complete methylatation patterns were found in oocytes at all 3 developmental stages. In embryos, an average methylation pattern of 53% was found, indicating that the imprints, which had been set during gametogenesis, are stably maintained in the preimplantation embryo. Geuns et al. (2003) concluded that the maternal imprints for the imprint control region of the SNRPN gene are already reestablished at the germinal vesicle stage, and are not reestablished in a late oocyte stage or after fertilization, as had been previously reported.

Kantor et al. (2004) constructed a transgene including both the 4.3-kb PWS-SRO sequence and the 880-bp AS-SRO sequence and determined that the transgene carried out the entire imprinting process. The epigenetic features of this transgene resembled those previously observed on the endogenous locus, thus allowing analyses in mouse gametes and early embryos. In gametes, they identified a differentially methylated CpG cluster (DMR) on AS-SRO that was methylated in sperm and unmethylated in oocytes. This DMR specifically bound a maternal allele-discrimination protein that was involved in DMR maintenance through implantation when methylation of PWS-SRO the maternal allele takes place. While the AS-SRO was required in gametes to confer methylation on PWS-SRO, it was dispensable later in development.

The SNRPN 5-prime region colocalizes with the PWS imprinting center and contains 2 DNase I hypersensitive sites, DHS1 at the SNRPN promoter and DHS2 within intron 1, exclusively on the paternally inherited chromosome. Rodriguez-Jato et al. (2005) examined DHS1 and DHS2 to identify cis- and trans-acting regulatory elements within the endogenous SNRPN 5-prime region. Analysis of DHS1 by in vivo footprinting and chromatin immunoprecipitation identified allele-specific interactions with multiple regulatory proteins, including NRF1 (600879), which regulates genes involved in mitochondrial and metabolic functions. DHS2 acted as an enhancer of the SNRPN promoter and contained a highly conserved region that showed allele-specific interactions with unphosphorylated RNA polymerase II (see 180660), YY1 (600013), Sp1 (189906), and NRF1, further suggesting a key role for NRF1 in regulation of the SNRPN locus.

In mouse and humans, several alternative exons expressed from upstream alternative promoters of the Snrpn gene are expressed as IC transcripts (Bressler et al., 2001). However, there is no similarity between the nucleotide sequences of human and mouse IC transcripts. In mice, Mapendano et al. (2006) found strong expression of Snrpn IC transcripts in brain and ovary but not in other tissues. Expression levels in the brain were 7-fold higher compared to those in ovaries. In situ hybridization signals were observed in oocytes and granulosa cells of the secondary and developing follicles. Mapendano et al. (2006) suggested that the IC transcript may be associated with the establishment of PWS-IC methylation on the maternal chromosome as an AS-IC cis-acting element.


Cytogenetics

Sun et al. (1996) reported a patient with the PWS phenotype and a balanced reciprocal translocation t(15;19)(q12;q13.41), which was paternal in origin. By FISH analysis and examination of DNA by Southern blot hybridization, they found that the translocation breakpoint occurred between exons 0 and 1 of the SNRPN locus, outside of the SmN open reading frame. Sun et al. (1996) reported that the transcriptional activities of ZNF127 (MKRN3; 603856), IPW, PAR1 (600161), and PAR5 (600162) were detected with RT-PCR from fibroblasts of this patient, whereas transcription from only the first 2 exons and the last 7 exons of SNRPN was detected with RT-PCR. The complete SNRPN mRNA (10 exons) was not detected. Sun et al. (1996) suggested that the putative SNURF sequence would be interrupted in this patient, and this disruption may play a role in the etiology of the PWS phenotype.

Kuslich et al. (1999) likewise identified a de novo balanced translocation in a Prader-Willi syndrome patient: (4;15)(q27;q11.2)pat. The breakpoints lay between SNRPN exons 2 and 3. Parental-origin studies indicated that there was no uniparental disomy and no apparent deletion. The patient expressed ZNF127, SNRPN exons 1 and 2, IPW, and PAR1, but did not express either SNRPN exons 3 and 4 or PAR5, as assayed by RT-PCR, of peripheral blood cells. Kuslich et al. (1999) concluded that this patient and that reported by Sun et al. (1996) supported the contention that an intact genomic region and/or transcription of SNRPN exons 2 and 3 play a pivotal role in the manifestations of the major clinical phenotype in PWS.

Schulze et al. (1996) presented evidence suggesting that SNRPN is not a major determinant of the Prader-Willi syndrome. They mapped the breakpoint of balanced translocation (9;15)pat associated with most of the PWS features to a region between SNRPN and PAR1. Methylation and expression studies indicated that the paternal SNRPN allele was unaffected by the translocation, while IPW and PAR1 were unexpressed. This focused attention on genes distal to the breakpoint as the main candidate for PWS genes and was considered consistent with a cis action of the putative imprinting center (IC) gene located proximal to SNRPN (Sutcliffe et al., 1994; Buiting et al., 1995). Schulze et al. (1996) suggested that further studies of translocational disruption of the imprinted region may establish genotype/phenotype relationships in Prader-Willi syndrome, which they presumed to be a contiguous gene syndrome.

Balanced translocations affecting the paternal copy of 15q11-q13 have been proven to be a rare cause of Prader-Willi syndrome (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 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 and PAR1, were not expressed in the patient. The authors suggested that lack of expression of these sequences may contribute to the PWS phenotype.

Gallagher et al. (2002) suggested that the minimal critical region for PWS is approximately 121 kb within the SNRPN locus of more than 460 kb, bordered by a breakpoint cluster region identified in 3 individuals with PWS who had balanced reciprocal translocations and by the proximal deletion breakpoint of a familial deletion found in an unaffected mother, her 3 children with AS, and her father. The subset of SNRPN-encoded snoRNAs within this region comprises the PWCR1/HBII-85 (SNORD116-1; 605436) cluster of snoRNAs and the single HBII-438A snoRNA. These are the only known genes within this region, which suggests that loss of their expression may be responsible for much or all of the phenotype of PWS. This hypothesis is challenged by findings in 2 individuals with PWS who had balanced translocations with breakpoints upstream of the proposed minimal critical region but whose cells were reported to express transcripts within it, adjacent to these snoRNAs. By use of real-time quantitative RT-PCR, Gallagher et al. (2002) reassessed expression of these transcripts and of the snoRNAs themselves in fibroblasts of 1 of these patients. They found that the transcripts reported to be expressed in lymphoblast-somatic cell hybrids were not expressed in fibroblasts, and they suggested that the original results were misinterpreted. Most important, they showed that the PWCR1/HBII-85 snoRNAs were not expressed in fibroblasts of this individual. These results were consistent with the hypothesis that loss of expression of the snoRNAs in the proposed minimal critical region confers much or all of the phenotype of PWS.


Molecular Genetics

In 2 sibs with the typical phenotype of PWS but without a cytogenetically detectable deletion in 15q, Ishikawa et al. (1996) demonstrated deletion of SNRPN by fluorescence in situ hybridization.

Bielinska et al. (2000) reported a PWS family in which the father was mosaic for an imprinting center deletion on his paternal chromosome. The deletion chromosome had acquired a maternal methylation imprint in his somatic cells. Identical observations were made in chimeric mice generated from 2 independent embryonic stem cell lines harboring a similar deletion. Bielinska et al. (2000) concluded that the Prader-Willi syndrome imprinting center element is not only required for the establishment of the paternal imprint, but also for its postzygotic maintenance.


Animal Model

The SNRPN promoter is embedded in a CpG island that is maternally methylated, is expressed only from the paternal chromosome, and lies within an imprinting center that is required for switching to and/or maintenance of the paternal epigenotype. In mice and humans, the SNRPN gene, as well as other loci in the region, are subject to genomic imprinting. Bressler et al. (2001) showed that a 0.9-kb deletion of exon 1 of mouse Snrpn did not disrupt imprinting or elicit any obvious phenotype, although it did allow the detection of previously unknown upstream exons. In contrast, a larger, overlapping 4.8-kb deletion caused a partial or mosaic imprinting defect and perinatal lethality when paternally inherited.

As part of studies of genomic imprinting in the Prader-Willi/Angelman domain, Tsai et al. (2002) inserted an agouti coat color cassette into the downstream open reading frame (ORF) of the Snurf-Snrpn locus in the mouse. The fusion gene was maternally silenced, as is Snurf-Snrpn, and produced a tan abdomen only when inherited paternally in otherwise black mice. A screen for dominant epigenetic or genetic events was performed with ENU mutagenesis, using a strategy whereby variation in abdominal color was scored at weaning. One mouse with maternal origin of the fusion gene had a tan abdomen and had an imprinting defect resulting in loss of both maternal methylation and silencing of the fusion gene. One mouse with paternal origin of the fusion gene was completely yellow and was found to have an ATG-to-AAG mutation in the initiation codon of the upstream ORF encoding Snurf. Northern blotting, immunoblotting, and transfection studies demonstrated that the mutation caused a 15-fold increase in translation of the downstream ORF in 2 fusion constructs, leading the authors to suggest that similar translational control may affect the normal Snurf-Snrpn transcript as well.

Peery et al. (2007) generated 2 deletions in mouse at a location analogous to that of the human AS-IC upstream of the SNRPN gene. Neither deletion produced an imprinting defect, suggesting that the location of the AS-IC is not strictly conserved between human and mouse.

Superovulation (ovarian stimulation) is an assisted reproductive technology (ART) for human subfertility/infertility treatment, which has been correlated with increased frequencies of imprinting disorders such as Angelman (105830) and Beckwith-Wiedemann syndromes (130650). Market-Velker et al. (2010) examined the effects of superovulation on genomic imprinting in individual mouse blastocyst stage embryos. Superovulation perturbed genomic imprinting of both maternally and paternally expressed genes. Loss of Snrpn, Peg3 (601483), and Kcnq1ot1 (604115) and gain of H19 (103280) imprinted methylation were observed. This perturbation was dose-dependent, with aberrant imprinted methylation more frequent at higher hormone dosage. Maternal as well as paternal H19 methylation was perturbed by superovulation. Market-Velker et al. (2010) postulated that superovulation may have dual effects during oogenesis, disrupting acquisition of imprints in growing oocytes, as well as maternal-effect gene products subsequently required for imprint maintenance during preimplantation development.


REFERENCES

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  26. Saitoh, S., Wada, T. Parent-of-origin specific histone acetylation and reactivation of a key imprinted gene locus in Prader-Willi syndrome. Am. J. Hum. Genet. 66: 1958-1962, 2000. [PubMed: 10775525, related citations] [Full Text]

  27. Schmauss, C., McAllister, G., Ohosone, Y., Hardin, J. A., Lerner, M. R. A comparison of snRNP-associated Sm-autoantigens: human N, rat N and human B/B-prime. Nucleic Acids Res. 17: 1733-1743, 1989. Note: Erratum: Nucleic Acids Res. 17: 6777 only, 1989. [PubMed: 2522186, related citations] [Full Text]

  28. Schulze, A., Hansen, C., Skakkebaek, N. E., Brondum-Nielsen, K., Ledbetter, D. H., Tommerup, N. Exclusion of SNRPN as a major determinant of Prader-Willi syndrome by a translocation breakpoint. Nature Genet. 12: 452-454, 1996. [PubMed: 8630505, related citations] [Full Text]

  29. Schweizer, J., Zynger, D., Francke, U. In vivo nuclease hypersensitivity studies reveal multiple sites of parental origin-dependent differential chromatin conformation in the 150 kb SNRPN transcription unit. Hum. Molec. Genet. 8: 555-566, 1999. [PubMed: 10072422, related citations] [Full Text]

  30. Shemer, R., Hershko, A. Y., Perk, J., Mostoslavsky, R., Tsuberi, B., Cedar, H., Buiting, K., Razin, A. The imprinting box of the Prader-Willi/Angelman syndrome domain. Nature Genet. 26: 440-443, 2000. [PubMed: 11101841, related citations] [Full Text]

  31. Sun, Y., Nicholls, R. D., Butler, M. G., Saitoh, S., Hainline, B. E., Palmer, C. G. Breakage in the SNRPN locus in a balanced 46,XY,t(15;19) Prader-Willi syndrome patient. Hum. Molec. Genet. 5: 517-524, 1996. [PubMed: 8845846, related citations] [Full Text]

  32. Sutcliffe, J. S., Nakao, M., Christian, S., Orstavik, K. H., Tommerup, N., Ledbetter, D. H., Beaudet, A. L. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nature Genet. 8: 52-58, 1994. [PubMed: 7987392, related citations] [Full Text]

  33. Tsai, T.-F., Chen, K.-S., Weber, J. S., Justice, M. J., Beaudet, A. L. Evidence for translational regulation of the imprinted Snurf-Snrpn locus in mice. Hum. Molec. Genet. 11: 1659-1668, 2002. [PubMed: 12075010, related citations] [Full Text]

  34. Wawrzik, M., Spiess, A.-N., Herrmann, R., Buiting, K., Horsthemke, B. Expression of SNURF-SNRPN upstream transcripts and epigenetic regulatory genes during human spermatogenesis. Europ. J. Hum. Genet. 17: 1463-1470, 2009. [PubMed: 19471314, images, related citations] [Full Text]

  35. 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, related citations] [Full Text]


Patricia A. Hartz - updated : 3/10/2015
Patricia A. Hartz - updated : 8/15/2014
George E. Tiller - updated : 11/12/2010
Patricia A. Hartz - updated : 8/28/2009
Patricia A. Hartz - updated : 11/29/2007
George E. Tiller - updated : 5/30/2007
Matthew B. Gross - reorganized : 5/16/2006
Matthew B. Gross - updated : 5/16/2006
Cassandra L. Kniffin - updated : 4/28/2006
George E. Tiller - updated : 1/11/2006
George E. Tiller - updated : 6/2/2003
Victor A. McKusick - updated : 10/7/2002
Victor A. McKusick - updated : 6/25/2001
George E. Tiller - updated : 4/17/2001
Victor A. McKusick - updated : 7/26/2000
Ada Hamosh - updated : 4/28/2000
Victor A. McKusick - updated : 6/2/1999
Victor A. McKusick - updated : 5/14/1999
Victor A. McKusick - updated : 2/8/1999
Victor A. McKusick - updated : 3/5/1998
Moyra Smith - updated : 10/2/1996
Moyra Smith - updated : 5/14/1996
Creation Date:
Victor A. McKusick : 1/26/1993
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terry : 11/22/2000
carol : 8/1/2000
terry : 7/26/2000
alopez : 6/9/2000
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terry : 4/28/2000
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jlewis : 6/8/1999
jlewis : 6/8/1999
terry : 6/2/1999
mgross : 5/25/1999
mgross : 5/19/1999
terry : 5/14/1999
carol : 2/14/1999
terry : 2/8/1999
alopez : 3/24/1998
terry : 3/5/1998
terry : 7/7/1997
mark : 11/7/1996
terry : 10/3/1996
terry : 10/2/1996
mark : 10/2/1996
mark : 8/14/1996
carol : 5/14/1996
terry : 4/19/1996
mark : 4/9/1996
terry : 4/5/1996
mimadm : 3/25/1995
terry : 5/5/1994
carol : 3/11/1994
carol : 1/26/1993

* 182279

SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE N; SNRPN


Alternative titles; symbols

SMN


Other entities represented in this entry:

SNRPN UPSTREAM READING FRAME, INCLUDED; SNURF, INCLUDED

HGNC Approved Gene Symbol: SNRPN

Cytogenetic location: 15q11.2     Genomic coordinates (GRCh38): 15:24,823,637-24,978,723 (from NCBI)


TEXT

Description

SNRPN, or SNURF-SNRPN, is a bicistronic imprinted gene that encodes 2 polypeptides, the SmN splicing factor, which is involved in RNA processing, and the SNRPN upstream reading frame (SNURF) polypeptide. The SNRPN gene is transcribed exclusively from the paternally inherited chromosome and shows highest expression in brain and heart. SNRPN is located within an imprinted gene cluster in chromosome 15 that is associated with Prader-Willi syndrome (PWS; 176270) and Angelman syndrome (AS; 105830), 2 clinically distinct neurogenetic disorders. PWS arises from loss of function of genes in this region expressed exclusively from the paternal chromosome, suggesting that SNRPN may play a role in its etiology (Rodriguez-Jato et al., 2005).


Cloning and Expression

Small nuclear ribonucleoprotein particles (snRNP) found in spliceosomes contain small RNAs U1 (180680), U2 (180690), U4, U5 (180691), and U6 (180692), and associated polypeptides. Some of these polypeptides are present in all 5 of these snRNPs and others are unique to U1 or U2 snRNPs or have tissue-limited expression patterns. SnRNP-associated proteins have epitopes that react with autoimmune sera. With such an antiserum (Sm), a protein termed SmN was identified and the gene subsequently cloned (McAllister et al., 1988; Li et al., 1989; Schmauss et al., 1989). Although the sequence of SmN shows it to be highly homologous to the ubiquitous core snRNP protein B and its alternatively spliced form B-prime, Ozcelik et al. (1992) noted that SmN is expressed predominantly in brain and especially in central neurons. They suggested that SmN may be involved in brain-specific mRNA splicing.

SNRPN Upstream Reading Frame (SNURF)

Sun et al. (1996) reported a patient with PWS phenotype and a balanced reciprocal translocation t(15;19)(q12;q13.41) of paternal origin in which the breakpoint occurred between exons 0 and 1 of the SNRPN locus, outside of the SmN open reading frame. Based on their findings, Sun et al. (1996) suggested that the 3 upstream exons (exons -1, 0, and 1) of SNRPN encode an additional independent reading frame, SNURF (SNRPN upstream reading frame).

Polycistronic transcripts are common in prokaryotes but rare in eukaryotes. Gray et al. (1999) found that 5 eutherian mammals (cow, rat, mouse, rabbit, and human) have the highly conserved SNURF coding sequence. The vast majority of nucleotide substitutions in SNURF were found to be in the wobble codon position, providing strong evolutionary evidence for selection for protein-coding function. Because SNURF-SNRPN maps to human chromosome 15q11-q13 and is paternally expressed, each cistron is a candidate for a role in the imprinted PWS and PWS mouse models. SNURF encodes a highly basic 71-amino acid protein that is nuclear-localized (as is the product of the SNRPN gene). Because SNURF is the only protein-coding sequence within the imprinting regulatory region in 15q11-q13, it may have provided the original selection for imprinting in this domain. Whereas some human tissues express a minor SNURF-only transcript, mouse tissues express only the bicistronic Snurf-Snrpn transcript. Gray et al. (1999) showed that both SNURF and SNRPN are translated in normal, but not PWS, human and mouse tissues and cell lines. These findings identified SNURF as a protein that is produced along with SNRPN from a bicistronic transcript; polycistronic mRNAs, therefore, are encoded in mammalian genomes where they may form functional operons.

By database analysis, Wawrzik et al. (2009) identified several novel transcripts from the SNURF-SNRPN region, 1 of which included exon 23 from the upstream PWRN1 gene (611215). Exon connection PCR analysis of fetal brain and testis detected 4 transcripts, including 2 that showed splicing between a 3-prime PWRN1 exon and SNURF-SNRPN exons. Wawrzik et al. (2009) suggested that PWNR1 is not an independent gene, but an alternative 5-prime part of SNURF-SNRPN. They also identified a transcript of unknown identity from this region, represented in GenBank as BC035402, that was upregulated in testis at meiosis.

UBE3A Antisense Transcript

Runte et al. (2001) reported that a long processed antisense transcript of UBE3A (601623) starts at the imprinting center (IC) at the 5-prime end of the SNURF-SNRPN gene. For further information on this antisense transcript, see SNHG14 (616259).


Gene Structure

Runte et al. (2001) determined that the SNURF-SNRPN core gene has 10 exons. Exons 1 through 3 encode SNURF, and exons 4 through 10 encode SNRPN. Upstream exon U5 includes the AS-IC element, whereas exon 1 includes the PWS-IC element.

For further information on the transcriptional unit that includes SNURF-SNRPN, see SNHG14 (616259).


Mapping

By study of somatic cell hybrids and hybrid cell lines, Ozcelik et al. (1992) mapped the SNRPN gene to chromosome 15q12 and a processed pseudogene, SNRPNP1, to chromosome 6pter-p21. Furthermore, they showed that SNRPN maps to the minimal deletion interval that is critical for Prader-Willi syndrome.

Mutirangura et al. (1993) constructed a complete YAC contig of the Prader-Willi/Angelman syndrome chromosome region and localized the SNRPN gene to specific YACs within the contig.

Leff et al. (1992) showed that the mouse Snrpn gene maps to chromosome 7 in a region of homology with human chromosome 15q11-q13.


Gene Function

Imprinting of SNRPN

Leff et al. (1992) demonstrated that the Snrpn gene is maternally imprinted in the mouse, suggesting that loss of the paternally derived SNRPN allele may be involved in the PWS phenotype. Cattanach et al. (1992) reported observations indicating that maternal duplication of the central part of mouse chromosome 7, where the Snrpn gene is located, causes an imprinting effect that may correspond to PWS. Paternal duplication was not associated with any detectable effect that might correspond with Angelman syndrome.

Glenn et al. (1993) demonstrated functional imprinting of the human SNRPN gene using RT-PCR. No expression was observed in cultured skin fibroblasts of patients with Prader-Willi syndrome but was found in all patients with Angelman syndrome and in normal controls. Glenn et al. (1993) also demonstrated a parent-specific DNA methylation imprint within intron 5 of the SNRPN gene, which suggested an epigenetic mechanism by which parent-specific expression of this gene might be inherited. Thus, the authors found that the pattern of imprinting fulfills 1 major criterion for SNRPN being involved in pathogenesis of PWS.

Reed and Leff (1994) characterized a sequence polymorphism within expressed portions of the human SNRPN gene and showed that the SNRPN gene is monoallelically expressed in fetal brain and heart and in adult brain. Analysis of maternal DNA and of SNRPN cDNA confirmed that the maternal allele is not expressed in fetal brain and heart. Thus, maternal imprinting of SNRPN supports the hypothesis that paternal absence of SNRPN is responsible for the PWS phenotype.

To examine the chromatin basis of imprinting in the 15q11-q13 region, Saitoh and Wada (2000) investigated the status of histone acetylation of the SNURF-SNRPN locus, which is a key imprinted gene in PWS. Chromatin immunoprecipitation studies showed that the unmethylated CpG island of the active, paternally derived allele associated with acetylated histones, whereas the methylated maternally derived, inactive allele was specifically hypoacetylated. The body of the SNURF-SNRPN gene was associated with acetylated histones on both alleles. Treatment of PWS cells with the DNA methyltransferase inhibitor 5-azadeoxycytidine induced demethylation of the SNURF-SNRPN CpG island and restored gene expression on the maternal allele. The reactivation was associated with increased H4 acetylation but not with H3 acetylation at the SNURF-SNRPN CpG island. These findings indicated that (1) a significant role for histone deacetylation in gene silencing is associated with imprinting in 15q11-q13, and (2) silenced genes in PWS can be reactivated by drug treatment. Thus, the potential for pharmaceutical treatment of imprinting-related disorders was raised.

Using Zfp57 (612192) mutant mice, Li et al. (2008) found that Zfp57 was required for maternal imprinting at the Snrpn locus in the female germline.

SNRPN-Associated Imprinting Center

Dittrich et al. (1996) reported the existence of an imprinting center, which maps to a 100-kb region of chromosome 15q11-q13. This imprinting center encodes alternative transcripts of the SNRPN gene. The novel exons lack protein coding potential and are expressed from the paternal chromosome only. They also reported that families with imprinting mutations have mutations in this transcription unit. Deletions and point mutations of the alternative 5-prime exons of SNRPN (referred to as BD transcripts) are associated with a block of the maternal-paternal imprint switch in several families with Angelman syndrome. Deletions of SNRPN exon 1 are associated with a block of the maternal-paternal imprint switch in several families with Prader-Willi syndrome. Based on their studies, Dittrich et al. (1996) proposed a model for imprint switching. In this model the imprint center consists of an imprinter and an imprint switch initiation site. The imprinter encodes the BD transcript. They proposed that the imprinter is transcribed from the paternal chromosome only and that it acts in cis on the switch initiation site (the SNRPN promoter, exon 1, or a site close by), possibly by introducing a change in chromatin structure.

Prader-Willi syndrome and Angelman syndrome are neurogenetic disorders caused by the lack of a paternal or a maternal contribution from human 15q11-q13, respectively. They involve oppositely imprinted genes: the paternally expressed PWS gene(s) and the maternally expressed AS gene. Deletions in the transcription unit of the imprinted SNRPN gene occur in patients who have PWS or Angelman syndrome because of a parental imprint switch failure in this chromosomal domain. It has been suggested that the SNRPN exon 1 region, which is deleted in PWS patients, contains an imprint switch element from which the maternal and paternal epigenotypes of the 15q11-q13 domain originate. Using the model organism Drosophila, Lyko et al. (1998) showed that a fragment from this region can function as a silencer in transgenic flies. Repression was detected specifically from this element and could not be observed with control human sequences. Additional experiments allowed the delineation of the silencer to a fragment of 215 bp containing the SNRPN promoter region. These results provide an additional link between genomic imprinting and an evolutionarily conserved silencing mechanism. Lyko et al. (1998) suggested that the identified element participates in the long-range regulation of the imprinted 15q11-q13 domain or locally represses SNRPN expression from the maternal allele.

Schweizer et al. (1999) studied the mechanism by which small microdeletions within the 5-prime region of the SNRPN transcription unit affect the transcriptional activity and methylation status of distant imprinted genes throughout 15q11-q13 in cis. They analyzed the chromatin structure of the 150-kb SNRPN transcription unit for DNaseI- and MspI-hypersensitive sites. Using an in vivo approach on lymphoblastoid cell lines from PWS and AS individuals, they discovered that exon 1 of the SNRPN gene is flanked by prominent hypersensitive sites on the paternal allele, but is completely inaccessible to nucleases on the maternal allele. In contrast, they identified several regions of increased nuclease hypersensitivity on the maternal allele, one of which coincides with the minimal microdeletion region for AS, and another that lies in intron 1 immediately downstream of the paternal-specific hypersensitive sites. At several sites, parental origin-specific nuclease hypersensitivity was found to be correlated with hypermethylation on the allele contributed by the other parent. Schweizer et al. (1999) suggested that the differential parental origin-dependent chromatin conformations may govern access of regulatory protein complexes and/or RNAs that mediate interaction of the region with other genes.

Several observations had suggested that cis elements within the AS-SRO (shortest region of overlap) and PWS-SRO constitute an imprinting box that regulates the entire domain on both chromosomes. Shemer et al. (2000) showed that a minitransgene composed of 200-bp Snrpn promoter/exon 1 and a 1-kb sequence located approximately 35 kb upstream to the SNRPN promoter confer imprinting as judged by differential methylation, parent-of-origin-specific transcription, and asynchronous replication.

Geuns et al. (2003) studied the methylation patterns of the imprint control region of the SNRPN gene in human spermatozoa, oocytes at the germinal vesicle, metaphase I, and metaphase II stages, and preimplantation embryos. In spermatozoa, almost all potential methylation sites were unmethylated, whereas near-complete methylatation patterns were found in oocytes at all 3 developmental stages. In embryos, an average methylation pattern of 53% was found, indicating that the imprints, which had been set during gametogenesis, are stably maintained in the preimplantation embryo. Geuns et al. (2003) concluded that the maternal imprints for the imprint control region of the SNRPN gene are already reestablished at the germinal vesicle stage, and are not reestablished in a late oocyte stage or after fertilization, as had been previously reported.

Kantor et al. (2004) constructed a transgene including both the 4.3-kb PWS-SRO sequence and the 880-bp AS-SRO sequence and determined that the transgene carried out the entire imprinting process. The epigenetic features of this transgene resembled those previously observed on the endogenous locus, thus allowing analyses in mouse gametes and early embryos. In gametes, they identified a differentially methylated CpG cluster (DMR) on AS-SRO that was methylated in sperm and unmethylated in oocytes. This DMR specifically bound a maternal allele-discrimination protein that was involved in DMR maintenance through implantation when methylation of PWS-SRO the maternal allele takes place. While the AS-SRO was required in gametes to confer methylation on PWS-SRO, it was dispensable later in development.

The SNRPN 5-prime region colocalizes with the PWS imprinting center and contains 2 DNase I hypersensitive sites, DHS1 at the SNRPN promoter and DHS2 within intron 1, exclusively on the paternally inherited chromosome. Rodriguez-Jato et al. (2005) examined DHS1 and DHS2 to identify cis- and trans-acting regulatory elements within the endogenous SNRPN 5-prime region. Analysis of DHS1 by in vivo footprinting and chromatin immunoprecipitation identified allele-specific interactions with multiple regulatory proteins, including NRF1 (600879), which regulates genes involved in mitochondrial and metabolic functions. DHS2 acted as an enhancer of the SNRPN promoter and contained a highly conserved region that showed allele-specific interactions with unphosphorylated RNA polymerase II (see 180660), YY1 (600013), Sp1 (189906), and NRF1, further suggesting a key role for NRF1 in regulation of the SNRPN locus.

In mouse and humans, several alternative exons expressed from upstream alternative promoters of the Snrpn gene are expressed as IC transcripts (Bressler et al., 2001). However, there is no similarity between the nucleotide sequences of human and mouse IC transcripts. In mice, Mapendano et al. (2006) found strong expression of Snrpn IC transcripts in brain and ovary but not in other tissues. Expression levels in the brain were 7-fold higher compared to those in ovaries. In situ hybridization signals were observed in oocytes and granulosa cells of the secondary and developing follicles. Mapendano et al. (2006) suggested that the IC transcript may be associated with the establishment of PWS-IC methylation on the maternal chromosome as an AS-IC cis-acting element.


Cytogenetics

Sun et al. (1996) reported a patient with the PWS phenotype and a balanced reciprocal translocation t(15;19)(q12;q13.41), which was paternal in origin. By FISH analysis and examination of DNA by Southern blot hybridization, they found that the translocation breakpoint occurred between exons 0 and 1 of the SNRPN locus, outside of the SmN open reading frame. Sun et al. (1996) reported that the transcriptional activities of ZNF127 (MKRN3; 603856), IPW, PAR1 (600161), and PAR5 (600162) were detected with RT-PCR from fibroblasts of this patient, whereas transcription from only the first 2 exons and the last 7 exons of SNRPN was detected with RT-PCR. The complete SNRPN mRNA (10 exons) was not detected. Sun et al. (1996) suggested that the putative SNURF sequence would be interrupted in this patient, and this disruption may play a role in the etiology of the PWS phenotype.

Kuslich et al. (1999) likewise identified a de novo balanced translocation in a Prader-Willi syndrome patient: (4;15)(q27;q11.2)pat. The breakpoints lay between SNRPN exons 2 and 3. Parental-origin studies indicated that there was no uniparental disomy and no apparent deletion. The patient expressed ZNF127, SNRPN exons 1 and 2, IPW, and PAR1, but did not express either SNRPN exons 3 and 4 or PAR5, as assayed by RT-PCR, of peripheral blood cells. Kuslich et al. (1999) concluded that this patient and that reported by Sun et al. (1996) supported the contention that an intact genomic region and/or transcription of SNRPN exons 2 and 3 play a pivotal role in the manifestations of the major clinical phenotype in PWS.

Schulze et al. (1996) presented evidence suggesting that SNRPN is not a major determinant of the Prader-Willi syndrome. They mapped the breakpoint of balanced translocation (9;15)pat associated with most of the PWS features to a region between SNRPN and PAR1. Methylation and expression studies indicated that the paternal SNRPN allele was unaffected by the translocation, while IPW and PAR1 were unexpressed. This focused attention on genes distal to the breakpoint as the main candidate for PWS genes and was considered consistent with a cis action of the putative imprinting center (IC) gene located proximal to SNRPN (Sutcliffe et al., 1994; Buiting et al., 1995). Schulze et al. (1996) suggested that further studies of translocational disruption of the imprinted region may establish genotype/phenotype relationships in Prader-Willi syndrome, which they presumed to be a contiguous gene syndrome.

Balanced translocations affecting the paternal copy of 15q11-q13 have been proven to be a rare cause of Prader-Willi syndrome (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 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 and PAR1, were not expressed in the patient. The authors suggested that lack of expression of these sequences may contribute to the PWS phenotype.

Gallagher et al. (2002) suggested that the minimal critical region for PWS is approximately 121 kb within the SNRPN locus of more than 460 kb, bordered by a breakpoint cluster region identified in 3 individuals with PWS who had balanced reciprocal translocations and by the proximal deletion breakpoint of a familial deletion found in an unaffected mother, her 3 children with AS, and her father. The subset of SNRPN-encoded snoRNAs within this region comprises the PWCR1/HBII-85 (SNORD116-1; 605436) cluster of snoRNAs and the single HBII-438A snoRNA. These are the only known genes within this region, which suggests that loss of their expression may be responsible for much or all of the phenotype of PWS. This hypothesis is challenged by findings in 2 individuals with PWS who had balanced translocations with breakpoints upstream of the proposed minimal critical region but whose cells were reported to express transcripts within it, adjacent to these snoRNAs. By use of real-time quantitative RT-PCR, Gallagher et al. (2002) reassessed expression of these transcripts and of the snoRNAs themselves in fibroblasts of 1 of these patients. They found that the transcripts reported to be expressed in lymphoblast-somatic cell hybrids were not expressed in fibroblasts, and they suggested that the original results were misinterpreted. Most important, they showed that the PWCR1/HBII-85 snoRNAs were not expressed in fibroblasts of this individual. These results were consistent with the hypothesis that loss of expression of the snoRNAs in the proposed minimal critical region confers much or all of the phenotype of PWS.


Molecular Genetics

In 2 sibs with the typical phenotype of PWS but without a cytogenetically detectable deletion in 15q, Ishikawa et al. (1996) demonstrated deletion of SNRPN by fluorescence in situ hybridization.

Bielinska et al. (2000) reported a PWS family in which the father was mosaic for an imprinting center deletion on his paternal chromosome. The deletion chromosome had acquired a maternal methylation imprint in his somatic cells. Identical observations were made in chimeric mice generated from 2 independent embryonic stem cell lines harboring a similar deletion. Bielinska et al. (2000) concluded that the Prader-Willi syndrome imprinting center element is not only required for the establishment of the paternal imprint, but also for its postzygotic maintenance.


Animal Model

The SNRPN promoter is embedded in a CpG island that is maternally methylated, is expressed only from the paternal chromosome, and lies within an imprinting center that is required for switching to and/or maintenance of the paternal epigenotype. In mice and humans, the SNRPN gene, as well as other loci in the region, are subject to genomic imprinting. Bressler et al. (2001) showed that a 0.9-kb deletion of exon 1 of mouse Snrpn did not disrupt imprinting or elicit any obvious phenotype, although it did allow the detection of previously unknown upstream exons. In contrast, a larger, overlapping 4.8-kb deletion caused a partial or mosaic imprinting defect and perinatal lethality when paternally inherited.

As part of studies of genomic imprinting in the Prader-Willi/Angelman domain, Tsai et al. (2002) inserted an agouti coat color cassette into the downstream open reading frame (ORF) of the Snurf-Snrpn locus in the mouse. The fusion gene was maternally silenced, as is Snurf-Snrpn, and produced a tan abdomen only when inherited paternally in otherwise black mice. A screen for dominant epigenetic or genetic events was performed with ENU mutagenesis, using a strategy whereby variation in abdominal color was scored at weaning. One mouse with maternal origin of the fusion gene had a tan abdomen and had an imprinting defect resulting in loss of both maternal methylation and silencing of the fusion gene. One mouse with paternal origin of the fusion gene was completely yellow and was found to have an ATG-to-AAG mutation in the initiation codon of the upstream ORF encoding Snurf. Northern blotting, immunoblotting, and transfection studies demonstrated that the mutation caused a 15-fold increase in translation of the downstream ORF in 2 fusion constructs, leading the authors to suggest that similar translational control may affect the normal Snurf-Snrpn transcript as well.

Peery et al. (2007) generated 2 deletions in mouse at a location analogous to that of the human AS-IC upstream of the SNRPN gene. Neither deletion produced an imprinting defect, suggesting that the location of the AS-IC is not strictly conserved between human and mouse.

Superovulation (ovarian stimulation) is an assisted reproductive technology (ART) for human subfertility/infertility treatment, which has been correlated with increased frequencies of imprinting disorders such as Angelman (105830) and Beckwith-Wiedemann syndromes (130650). Market-Velker et al. (2010) examined the effects of superovulation on genomic imprinting in individual mouse blastocyst stage embryos. Superovulation perturbed genomic imprinting of both maternally and paternally expressed genes. Loss of Snrpn, Peg3 (601483), and Kcnq1ot1 (604115) and gain of H19 (103280) imprinted methylation were observed. This perturbation was dose-dependent, with aberrant imprinted methylation more frequent at higher hormone dosage. Maternal as well as paternal H19 methylation was perturbed by superovulation. Market-Velker et al. (2010) postulated that superovulation may have dual effects during oogenesis, disrupting acquisition of imprints in growing oocytes, as well as maternal-effect gene products subsequently required for imprint maintenance during preimplantation development.


REFERENCES

  1. Bielinska, B., Blaydes, S. M., Buiting, K., Yang, T., Krajewska-Walasek, M., Horsthemke, B., Brannan, C. I. De novo deletions of SNRPN exon 1 in early human and mouse embryos result in a paternal to maternal imprint switch. Nature Genet. 25: 74-78, 2000. Note: Erratum: Nature Genet. 25: 241 only, 2000. [PubMed: 10802660] [Full Text: https://doi.org/10.1038/75629]

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Contributors:
Patricia A. Hartz - updated : 3/10/2015
Patricia A. Hartz - updated : 8/15/2014
George E. Tiller - updated : 11/12/2010
Patricia A. Hartz - updated : 8/28/2009
Patricia A. Hartz - updated : 11/29/2007
George E. Tiller - updated : 5/30/2007
Matthew B. Gross - reorganized : 5/16/2006
Matthew B. Gross - updated : 5/16/2006
Cassandra L. Kniffin - updated : 4/28/2006
George E. Tiller - updated : 1/11/2006
George E. Tiller - updated : 6/2/2003
Victor A. McKusick - updated : 10/7/2002
Victor A. McKusick - updated : 6/25/2001
George E. Tiller - updated : 4/17/2001
Victor A. McKusick - updated : 7/26/2000
Ada Hamosh - updated : 4/28/2000
Victor A. McKusick - updated : 6/2/1999
Victor A. McKusick - updated : 5/14/1999
Victor A. McKusick - updated : 2/8/1999
Victor A. McKusick - updated : 3/5/1998
Moyra Smith - updated : 10/2/1996
Moyra Smith - updated : 5/14/1996

Creation Date:
Victor A. McKusick : 1/26/1993

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