Evidence for the Role of PWCR1/HBII-85 C/D Box Small Nucleolar RNAs in Prader-Willi Syndrome

Abstract

Prior work has suggested that loss of expression of one or more of the many C/D box small nucleolar RNAs (snoRNAs) encoded within the complex, paternally expressed SNRPN (small nuclear ribonuclear protein N) locus may result in the phenotype of Prader-Willi syndrome (PWS). We suggest that the minimal critical region for PWS is approximately 121 kb within the >460-kb SNRPN locus, bordered by a breakpoint cluster region identified in three individuals with PWS who have balanced reciprocal translocations and by the proximal deletion breakpoint of a familial deletion found in an unaffected mother, her three children with Angelman syndrome, and her father. The subset of SNRPN-encoded snoRNAs within this region comprises the PWCR1/HBII-85 cluster of snoRNAs and the single HBII-438A snoRNA. These are the only known genes within this region, which suggests that loss of their expression may be responsible for much or all of the phenotype of PWS. This hypothesis is challenged by findings in two individuals with PWS who have balanced translocations with breakpoints upstream of the proposed minimal critical region but whose cells were reported to express transcripts within it, adjacent to these snoRNAs. By use of real-time quantitative reverse-transcriptase polymerase chain reaction, we reassessed expression of these transcripts and of the snoRNAs themselves in fibroblasts of one of these patients. We find that the transcripts reported to be expressed in lymphoblast-somatic cell hybrids are not expressed in fibroblasts, and we suggest that the original results were misinterpreted. Most important, we show that the PWCR1/HBII-85 snoRNAs are not expressed in fibroblasts of this individual. These results are consistent with the hypothesis that loss of expression of the snoRNAs in the proposed minimal critical region confers much or all of the phenotype of PWS.

Small nucleolar RNA expression profiling identifies potential prognostic markers in peripheral T-cell lymphoma

“…Apart from their role in ribosomal RNA maturation, only a few studies have investigated their pathologic implications. 20,23,25,33 We have demonstrated herein that snoRNAexpression profiles are relevant for PTCL prognostication. As miRNAs, snoRNAs are widely underexpressed in lymphoma cells compared with 2 sets of normal T cells.…”

Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader–Willi syndrome

“…[5][6][7]10,14 Microdeletions, responsible for 70% of cases, lead to loss of a number of paternally expressed genes (MKRN3, NECDIN, MAGEL2, SNURF-SNRPN, snoRNAs) within the interval. Mutations have not been identified in any single gene that can be implicated in the PWS phenotype.…”

Long nuclear-retained non-coding RNAs and allele-specific higher-order chromatin organization at imprinted snoRNA gene arrays

“…Indeed, most recent studies focused on snoRD116 genes as potential candidate genes (Ding et al, 2008;Gallagher et al, 2002;Sahoo et al, 2008;Schule et al, 2005;Skryabin et al, 2007;Wirth et al, 2001). However, it has never been demonstrated formally that PWS results from the lack of expression of snoRD166, or snoRD116-HG, or both.…”