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: 4.52). 03/2005; 116(3):228-30. DOI: 10.1007/s00439-004-1219-2
Source: PubMed

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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    • "Apart from several protein-coding genes, this locus harbors two large tandemly repeated clusters of C/D box snoRNAs: SNORD116 and SNORD115, with 24 and 47 gene copies, respectively, generated from introns of the U-UBE3A- AS long nonprotein coding RNA (the typical arrangement is one SNORD gene copy per intron; a few introns harbor two copies of SNORD116 genes) (Cavaille et al. 2001; Wirth et al. 2001; Yin et al. 2012). Although deletion of the SNORD116 gene cluster resembles key characteristics of the PWS-phenotype in patients and causes growth retardation in mice (Skryabin et al. 2007; Ding et al. 2008; Sahoo et al. 2008; de Smith et al. 2009), SNORD115 deletion appears to lack a phenotype (Runte et al. 2005). Snord115 and Snord116 belong to a subclass termed " orphan " snoRNAs as they lack apparent base complementarities to common RNA targets, suggesting functions apart from rRNA and snRNA processing (Bachellerie et al. 2002). "
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    ABSTRACT: The evolution of new genes can ensue through either gene duplication and the neofunctionalization of one of the copies or the formation of a de novo gene from hitherto nonfunctional, neutrally evolving intergenic or intronic genomic sequences. Only very rarely are entire genes created de novo. Mostly, nonfunctional sequences are coopted as novel parts of existing genes, such as in the process of exonization whereby introns become exons through changes in splicing. Here, we report a case in which a novel non-protein coding RNA evolved by intron-sequence recruitment into their structures. cDNAs derived from rat brain small RNAs, revealed a novel snoRNA originating from one of the Snord115 copies in the rat Prader-Willi-Syndrome locus. We suggest that a single point substitution in the Snord115 region led to the expression of a longer snoRNA variant, designated as L-Snord115. Cell culture and footprinting experiments confirmed that a single nucleotide substitution at Snord115 position 67 destabilized the kink-turn (K-turn) motif within the canonical snoRNA, while distal intronic sequences provided an alternate D-box region. The exapted sequence displays putative base pairing to 28S rRNA and mRNA targets.
    Genome Biology and Evolution 10/2013; 5(11). DOI:10.1093/gbe/evt155 · 4.53 Impact Factor
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    • "Another potentially important snoRNA in the PWS imprinting region is SNORD115, although there is currently no probe for SNORD115 in either MS-MLPA kit. Deletion of the SNORD115 snoRNA alone does not appear to cause PWS; however, its known role in isoform production of a serotonin receptor (Kishore and Stamm, 2006) may influence the PWS phenotype (Runte et al., 2005) and justifies the addition of a SNORD115 probe to the MS-MLPA-PWS/AS kits. Overall, we conclude that analysis of subjects with 15q11- q13 deletions can be carried out successfully using the A1 kit as it provides better characterization of large, more typically sized PWS and AS deletions. "
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    ABSTRACT: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are complex neurodevelopmental disorders caused by loss of expression of imprinted genes from the 15q11-q13 region depending on the parent of origin. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) kits from MRC-Holland (Amsterdam, The Netherlands) were used to detect PWS and AS deletion subtypes. We report our experience with two versions of the MS-MLPA-PWS/AS kit (original A1 and newer B1) in determining methylation status and deletion subtypes in individuals with PWS. MS-MLPA analysis was performed on DNA isolated from a large cohort of PWS subjects with the MS-MLPA-PWS/AS-A1 and -B1 probe sets. Both MS-MLPA kits will identify deletions in the 15q11-q13 region but the original MS-MLPA-A1 kit has a higher density of probes at the telomeric end of the 15q11-q13 region, which is more useful for identifying individuals with atypical deletions. The newer B1 kit contains more probes in the imprinting center (IC) and adjoining small noncoding RNAs useful in identifying small microdeletions. The A1 kit identified the typical deletions and smaller atypical deletions, whereas the B1 kit was more informative for identifying microdeletions including the IC and SNORD116 regions. Both kits should be made available for accurate characterization of PWS/AS deletion subtypes as well as evaluating for IC and SNORD116 microdeletions.
    Genetic Testing and Molecular Biomarkers 10/2011; 16(3):178-86. DOI:10.1089/gtmb.2011.0115 · 1.15 Impact Factor
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    • "Previous studies have shown that the maternally imprinted snoRNA, HBII-52, can alter both the splicing and editing of 5HT 2C transcripts (Kishore and Stamm, 2006), providing a provoking and straightforward mechanism by which to link the 5HT 2C-VGV mutation with the 15q11-13 locus and multiple aspects of this disorder. However, several clinical cases have been identified recently that either suggest deletion of this snoRNA is not sufficient to cause a PWS-like phenotype (Runte et al., 2005) or that a specific paternal deletion of the HBII-85 snoRNA cluster can result in PWS (de Smith et al., 2009; Gallagher et al., 2002; Sahoo et al., 2008). Due to the nature of these human clinical studies however, it was impossible to assess potential changes in the brain-specific expression of other snoRNAs in these patients, negating the ability of such studies to conclusively eliminate a role for HBII-52. "
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    ABSTRACT: RNA transcripts encoding the 2C-subtype of serotonin (5HT(2C)) receptor undergo up to five adenosine-to-inosine editing events to encode twenty-four protein isoforms. To examine the effects of altered 5HT(2C) editing in vivo, we generated mutant mice solely expressing the fully-edited (VGV) isoform of the receptor. Mutant animals present phenotypic characteristics of Prader-Willi syndrome (PWS) including a failure to thrive, decreased somatic growth, neonatal muscular hypotonia, and reduced food consumption followed by post-weaning hyperphagia. Though previous studies have identified alterations in both 5HT(2C) receptor expression and 5HT(2C)-mediated behaviors in both PWS patients and mouse models of this disorder, to our knowledge the 5HT(2C) gene is the first locus outside the PWS imprinted region in which mutations can phenocopy numerous aspects of this syndrome. These results not only strengthen the link between the molecular etiology of PWS and altered 5HT(2C) expression, but also demonstrate the importance of normal patterns of 5HT(2C) RNA editing in vivo.
    Neurobiology of Disease 08/2010; 39(2):169-80. DOI:10.1016/j.nbd.2010.04.004 · 5.20 Impact Factor
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