Exclusion of the C/D box snoRNA gene cluster HBII-52 from a major role in Prader-Willi syndrome. Hum Genet

Institut für Humangenetik, Universitätsklinikum Essen, Hufelandstrasse 55, 45122, Essen, Germany.
Human Genetics (Impact Factor: 4.82). 03/2005; 116(3):228-30. DOI: 10.1007/s00439-004-1219-2
Source: PubMed


Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurogenetic disorders caused by the loss of function of imprinted genes in 15q11-q13. The maternally expressed UBE3A gene is affected in AS. Four protein-encoding genes (MKRN3, MAGEL2, NDN and SNURF-SNRPN) and several small nucleolar (sno) RNA genes (HBII-13, HBII-436, HBII-85, HBII-438A, HBII-438B and HBII-52) are expressed from the paternal chromosome only but their contribution to PWS is unclear. To examine the role of the HBII-52 snoRNA genes, we have reinvestigated an AS family with a submicroscopic deletion spanning UBE3A and flanking sequences. By fine mapping of the centromeric deletion breakpoint in this family, we have found that the deletion affects all of the 47 HBII-52 genes. Since the complete loss of the HBII-52 genes in family members who carry the deletion on their paternal chromosome is not associated with an obvious clinical phenotype, we conclude that HBII-52 snoRNA genes do not play a major role in PWS. However, we cannot exclude the possibility that the loss of HBII-52 has a phenotypic effect when accompanied by the loss of function of other genes in 15q11-q13.

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    • "Although the involvement of SNORD115 in PWS syndrome is questionable, as loss of the snoRNA cluster does not lead to PWS phenotype1724, an antisense element within SNORD115 is complementary to an alternatively spliced exon of the 5HT-2C serotonin receptor pre-mRNA. The snoRNA target region is located within a sequence that is subject to post-transcriptional editing4. "
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    ABSTRACT: Prader-Willi Syndrome (PWS) is a neurogenetic disorder caused by the deletion of imprinted genes on the paternally inherited human chromosome 15q11-q13. This locus harbours a long non-protein-coding RNA (U-UBE3A-ATS) that contains six intron-encoded snoRNAs, including the SNORD116 and SNORD115 repetitive clusters. The 3'-region of U-UBE3A-ATS is transcribed in the cis-antisense direction to the ubiquitin-protein ligase E3A (UBE3A) gene. Deletion of the SNORD116 region causes key characteristics of PWS. There are few indications that SNORD115 might regulate serotonin receptor (5HT2C) pre-mRNA processing. Here we performed quantitative real-time expression analyses of RNAs from the PWS locus across 20 human tissues and combined it with deep-sequencing data derived from Cap Analysis of Gene Expression (CAGE-seq) libraries. We found that the expression profiles of SNORD64, SNORD107, SNORD108 and SNORD116 are similar across analyzed tissues and correlate well with SNORD116 embedded U-UBE3A-ATS exons (IPW116). Notable differences in expressions between the aforementioned RNAs and SNORD115 together with the host IPW115 and UBE3A cis-antisense exons were observed. CAGE-seq analysis revealed the presence of potential transcriptional start sites originated from the U-UBE3A-ATS spanning region. Our findings indicate novel aspects for the expression regulation in the PWS locus.
    Scientific Reports 09/2014; 4:6445. DOI:10.1038/srep06445 · 5.58 Impact Factor
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    • "The clinical symptoms of PWS include neonatal hypotonia, feeding difficulties and failure to thrive during infancy, excessive weight gain after 18 months, hyperphagia, hypogonadism, global developmental delay and equivocal facial features. Deletion of the HBII-85 snoRNA cluster results in an exhibition of all major clinical symptoms of PWS in humans [15]–[17], but the role of the HBII-52 cluster in PWS has been difficult to define [11], [18]. The neuronal-specific HBII-52 snoRNAs have been reported to participate in the post-transcriptional regulation of the pre-mRNA encoding the 5-hydroxytryptamine 2C receptor (5-HT2CR), an important neurotransmission protein, including A-to-I RNA editing and alternative RNA splicing, with in vitro experiments [19]–[21]. "
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    ABSTRACT: Imprinted small nucleolar RNAs (snoRNAs) are only found in eutherian genomes and closely related to brain functions. A complex human neurological disease, Prader-Willi syndrome (PWS), is primarily attributed to the deletion of imprinted snoRNAs in chromosome 15q11-q13. Here we investigated the snoRNA repertoires in the PWS locus of 12 mammalian genomes and their evolution processes. A total of 613 imprinted snoRNAs were identified in the PWS homologous loci and the gene number was highly variable across lineages, with a peak in Euarchontoglires. Lineage-specific gene gain and loss events account for most extant genes of the HBII-52 (SNORD115) and the HBII-85 (SNORD116) gene family, and remarkable high gene-birth rates were observed in the primates and the rodents. Meanwhile, rapid sequence substitution occurred only in imprinted snoRNA genes, rather than their flanking sequences or the protein-coding genes located in the same imprinted locus. Strong selective constraints on the functional elements of these imprinted snoRNAs further suggest that they are subjected to birth-and-death evolution. Our data suggest that the regulatory role of HBII-52 on 5-HT2CR pre-mRNA might originate in the Euarchontoglires through adaptive process. We propose that the rapid evolution of PWS-related imprinted snoRNAs has contributed to the neural development of Euarchontoglires.
    PLoS ONE 06/2014; 9(6):e100329. DOI:10.1371/journal.pone.0100329 · 3.23 Impact Factor
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    • "They are involved in directing alternative splicing or site-specific methylation of substrate RNAs [31,32]. However, it is unclear whether they are important in cases of maternal duplications (such as the two cases in this report) as they were reported to be expressed from the paternal chromosome only [33]. "
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    ABSTRACT: Background The 15q11-q13 region contains many low copy repeats and is well known for its genomic instability. Several syndromes are associated with genomic imbalance or copy-number-neutral uniparental disomy. We report on two patients: Patient 1 is a boy with developmental delay and autism; and Patient 2 is a girl with developmental delay, hypotonia and dysmorphism. We performed analyses to delineate their dosage in the 15q region, determine whether the patients’ dosage correlates with phenotypic severity, and whether genes in the amplified regions are significantly associated with identified functional networks. Results For the proximal region of 15q, molecular cytogenetic analysis with Agilent oligonucleotide array showed a copy number of 3 for Patient 1 and a copy number of 4 for Patient 2. Fluorescent in situ hybridization analysis of Patient 2 showed two different populations of cells with different marker chromosomes. Methylation analysis of the amplified region showed that the extra copies of small nuclear ribonucleoprotein polypeptide N gene were of maternal origin. Phenotypic severity did not correlate with the size and dosage of 15q, or whether the amplification is interstitial or in the form of a supernumerary marker. Pathway analysis showed that in Patient 2, the main functional networks that are affected by the genes from the duplicated/triplicated regions are developmental disorder, neurological disease and hereditary disease. Conclusions The 15q11-q13 gains that were found in both patients could explain their phenotypic presentations. This report expands the cohort of patients for which 15q11-q13 duplications are molecularly characterized.
    Molecular Cytogenetics 05/2014; 7(1):32. DOI:10.1186/1755-8166-7-32 · 2.14 Impact Factor
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