Disease relevance of SNRPN

• Maternal imprinting of human SNRPN, a gene deleted in Prader-Willi syndrome [1].
• Paternal only expression of SNRPN has previously been demonstrated by use of cell lines from PWS patients (maternal allele only) and Angelman syndrome (AS) patients (paternal allele only) [2].
• Two ovarian teratomas and one mediastinal teratoma showed only methylated SNRPN, consistent with entry into meiosis [3].
• These results demonstrated that IGF2 and SNRPN imprinting is completely maintained in human uteri and leiomyomas and that increased expression of IGF2 is not due to biallelic expression [4].
• Abnormal imprinting of SNRPN is associated with the Angelman/Prader-Willi syndromes, and that of LIT1 and H19 with the Beckwith-Wiedemann syndrome [5].

Psychiatry related information on SNRPN

• In their original configurations, SNRPN and UBE3A are expressed from both alleles, implying that acquisition of imprinting occurred after their rearrangement and required the evolution of a control locus [6].
• To increase our understanding of the regulation of expression of this imprinted gene, we have developed single-cell-sensitive procedures for the analysis of expression of the SNRPN gene during early human development [7].
• The molecular investigation of 75 institutionalized individuals with severe to profound mental retardation resulted in the detection of 1 case with an abnormal methylation pattern of the SNRPN gene, corresponding to AS [8].
• RT84 Id was positively associated with antibodies to Sm-D peptide 1-20 and to Ro/SSA 60 kD peptide 304-324, but negatively associated with anti-dsDNA activity [9].

High impact information on SNRPN

• HaploChIP showed close correlation between the level of bound phosphorylated RNA polymerase II at the SNRPN locus and allele-specific expression [10].
• Moreover, we found that CpG-rich regions in SNURF-SNRPN and NDN, which in somatic tissues are methylated on the maternal allele, are hypomethylated in unfertilized human oocytes [11].
• In some patients, this is associated with a deletion of the SNURF-SNRPN exon 1 region inherited from the paternal grandmother and the presence of a maternal imprint on the paternal chromosome [11].
• The SNRPN promoter is not required for genomic imprinting of the Prader-Willi/Angelman domain in mice [12].
• Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals [13].

Chemical compound and disease context of SNRPN

• Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients [14].
• Valproic acid increases SMN levels in spinal muscular atrophy patient cells [15].
• Recent studies indicate that the protein affected in spinal muscular atrophy, SMN, plays a role in the assembly of a number of macromolecular complexes that function in the nucleus, interacting with its partner proteins via their arginine- and glycine-rich domains [16].

Biological context of SNRPN

• Methylation and expression studies indicate that the paternal SNRPN allele is unaffected by the translocation, while IPW and PAR1 are unexpressed [17].
• We have mapped the gene encoding the small nuclear RNA associated polypeptide SmN (SNRPN) to human chromosome 15q12 and a processed pseudogene SNRPNP1 to chromosome region 6pter-p21 [18].
• Maternal imprinting of SNRPN supports the hypothesis that paternal absence of SNRPN is responsible for the PWS phenotype [1].
• This suggests that imprint switching on human chromosome 15 may involve alternative SNRPN transcripts [19].
• Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene [2].

Anatomical context of SNRPN

• Imprinting analysis using reverse transcription-polymerase chain reaction of RNA from fibroblasts and lymphoblasts of deletion Prader-Willi and Angelman patients demonstrated imprinting of SNRPN with exclusive expression from the paternal allele, but E6-AP and PAR-2 were not imprinted in these cultured human cells [20].
• Our results indicate that the maternal imprints for the IC-region of the human SNRPN-gene are already re-established at the GV stage and that they are not re-established in a late oocyte stage or after fertilization as previously reported [21].
• This view is supported by our studies of the imprinted SNRPN gene in that cells with paternal allele-specific expression (lymphocytes and lymphoblasts) replicate SNRPN alleles asynchronously, whereas cells with a low level of expression (HeLa) replicate SNRPN later and with less allelic asynchrony [22].
• Methylation imprints of the imprint control region of the SNRPN-gene in human gametes and preimplantation embryos [21].
• The ability to analyze for imprinting and expression of SNRPN and other genes in this region in cultured human cells will be a valuable tool for analyzing the molecular basis of the Prader-Willi and Angelman syndromes, although imprinting may differ between cultured cells and tissues.(ABSTRACT TRUNCATED AT 250 WORDS)[20]

Associations of SNRPN with chemical compounds

• Treatment of the lymphoblastoid cells with trichostatin A, a histone deacetylase inhibitor, did not result in any changes to SNRPN expression or association of acetylated histones with exon 1 [23].
• On the silent allele, 5-aza-dC treatment altered SNRPN expression, but not association with acetylated histones, suggesting that histone acetylation is a secondary event in the process of gene reactivation by CpG demethylation [23].
• DNA methylation was evaluated after bisulfite modification, PCR amplification, and restriction digestion at a consistently methylated CpG dinucleotide within the 5' flanking region of the SNRPN gene [3].
• However, > 96% of all of the 23 5'-CG-3' dinucleotides around SNRPN exon 1 are methylated on the maternal chromosome and completely devoid of methylation on the paternal chromosome [24].
• As part of a study on DNA methylation patterns in the human genome, we have applied the bisulfite protocol of genomic sequencing to study all 5'-CG-3' dinucleotides around exon 1 of SNRPN and at the D15S63 locus, which contains a start site for alternative SNRPN transcripts possibly involved in imprint switching during gametogenesis [24].

Physical interactions of SNRPN

• The imprinted SNRPN locus is a complex transcriptional unit that encodes the SNURF and SmN polypeptides as well as multiple non-coding RNAs [25].
• METHODS: SNRPN expression was analyzed by reverse transcription coupled to polymerase chain reaction (RT-PCR) [26].

Regulatory relationships of SNRPN

• The allelic expression of small nuclear ribonucleoprotein N (SNRPN) was stringently regulated while that of multimembrane-spanning polyspecific transporter-like gene 1 (IMPT1) showed a large degree of variation [27].
• For example, the differentially methylated 5 -portion of the human SNRPN gene-a sequence element that controls imprinting in the Prader-Willi and Angelman syndromes' domain on chromosome 15q11- q13-has strong DNase-I hypersensitive sites on the unmethylated paternal chromosome (4) [28].
• Our findings are compatible with the assumption that imprinted UBE3A expression is regulated through the SNURF-SNRPN sense- UBE3A antisense transcript [29].

Other interactions of SNRPN

• For validation, the DNA sequence copy number changes of selected clones (SNRPN, CMYC, HER2, ZNF217) detected by aCGH were confirmed by fluorescence in situ hybridization (FISH) [30].
• Whether upregulation of SNRPN is caused by its biallelic expression remains undetermined because restriction fragment length polymorphisms (RFLP) sites were not informative in SNRPN and IGF2 [31].
• The histone deacetylase inhibitor Trichostatin A did not alter SNRPN expression, but did reverse silencing of IFNG in a MECP2-mutant-expressing clone [32].
• Paternal specific expression of the known imprinted genes SNRPN (small nuclear ribonucleoprotein-associated polypeptide N gene) and IPW (imprinted gene in the Prader-Willi syndrome region) was maintained in the A9 hybrids [33].
• Transfection with a methylated oligonucleotide decoy specifically blocked binding of MeCP2 to the SNURF/SNRPN promoter within 15q11-13 and significantly lowered the percentage of paired 15q11-13 alleles in SH-SY5Y cells [34].

Analytical, diagnostic and therapeutic context of SNRPN

• Transcription from the first two exons and last seven exons of the SNRPN gene was also detected with RT-PCR; however, the complete mRNA (10 exons) was not detected [35].
• Since transcriptional regulation by DNA methylation involves histone deacetylation, we explored whether differences in histone acetylation exist between the two parental alleles of SNRPN and other paternally expressed genes in the region by using a chromatin immunoprecipitation assay with antibodies against acetylated histones H3 and H4 [23].
• In contrast to several cDNA clones and RT-PCR products, however, the 3.4-kb transcript detected by Northern blot hybridization with a probe for the novel exons does not contain SNRPN [36].
• The asynchrony pattern was significantly higher in XP carriers and patients with all three coding loci analyzed and significantly lower in XP patients and carriers with the imprinted locus SNRPN than in the control group [37].
• Correct prenatal diagnoses were obtained in 24 out of 24 samples using the 5' SNRPN locus; 4 out of 15 using the ZNF127 locus; and 10 out of 18 using the PW71 locus [38].

References