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
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.
Available from: Tim Karl
- "Cavaille and co-workers discovered that SNORD116 in wild type-like mice is exclusively expressed in the brain and that it maps to chromosome 15q11–q13 in humans (Cavaille et al., 2000). This region and micro-deletions to the SNORD116 snoRNA cluster have been associated with the Prader–Willi syndrome (PWS) including the typical hyperphagia and obesity ((Sahoo et al., 2008; de Smith et al., 2009) but see also (Runte et al., 2005)). In line with this, SNORD116 is absent from the brain of patients with PWS and work utilising Snord116 knockout mice has suggested that the snoRNA Snord116 gene cluster is a critical element in PWS formation (Ding et al., 2008; Sahoo et al., 2008; de Smith et al., 2009). "
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ABSTRACT: Prader-Willi syndrome (PWS) is the predominant genetic cause of obesity in humans and is associated with several behavioural phenotypes such as altered motoric function, reduced activity, and learning disabilities. It can include mood instability and, in some cases, psychotic episodes. Recently, the Snord116 gene has been associated with the development of PWS, however, it's contribution to the behavioural aspects of the disease are unknown. Here we show that male and female mice lacking Snord116 on both alleles exhibit normal motor behaviours and exploration but do display task-dependent alterations to locomotion and anxiety-related behaviours. Sociability is well developed in Snord116 deficient mice as are social recognition memory, spatial working memory, and fear-associated behaviours. No sex-specific effects were found. In conclusion, the biallelic Snord116 deficiency mouse model exhibits particular endophenotypes with some relevance to PWS, suggesting partial face validity for the syndrome.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Neuropeptides 07/2015; 53. DOI:10.1016/j.npep.2015.06.009 · 2.64 Impact Factor
Available from: Zoltán Konthur
- "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
Available from: Yijun Zhang
- "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 –, but the role of the HBII-52 cluster in PWS has been difficult to define , . 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 –. "
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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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