Exclusion of the C/D box snoRNA gene cluster HBII-52 from a major role in Prader-Willi syndrome.
ABSTRACT 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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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. · 3.53 Impact Factor
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ABSTRACT: Angelman syndrome (AS) is characterized by severe intellectual disability with ataxia, epilepsy, and behavioral uniqueness. The underlining molecular deficit is the absence of the maternal copy of the imprinted UBE3A gene due to maternal deletions, which is observed in 70–75% of cases, and can be detected using fluorescent in situ hybridization (FISH) of the UBE3A region. Only a few familial AS cases have been reported with a complete deletion of UBE3A. Here, we report on siblings with AS caused by a microdeletion of 15q11.2-q12 encompassing UBE3A at the breakpoint of an inversion at 15q11.2 and 15q26.1. Karyotyping revealed an inversion of 15q, and FISH revealed the deletion of the UBE3A region. Array comparative genomic hybridization (CGH) demonstrated a 467 kb deletion at 15q11.2-q12, encompassing only UBE3A, SNORD115, and PAR1, and a 53 kb deletion at 15q26.1, encompassing a part of SLCO3A1. Their mother had a normal karyotype and array CGH detected no deletion of 15q11.2-q12, so we assumed gonadal mosaicism. This report describes a rare type of familial AS detected using the D15S10 FISH test. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 08/2014; 164(11). · 2.30 Impact Factor
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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. · 5.08 Impact Factor