Small Nucleolar Rnas Missing in the Prader Willi Syndrome

HBII-52 is a neuron-specific C/D box snoRNA (Cavaille et al. 2000). The snoRNA resides in the SNURF-SNRPN locus (Fig. 21.3a). Loss of expression from this locus is the most likely cause for Prader-Willi syndrome (PWS) (Butler et al. 2006).

In contrast to most other C/D box snoRNAs, HBII-52 contains only a single antisense box. This antisense box exhibits sequence complementarity to exon Vb of the 5-HT2C receptor and is phylogenetically highly conserved (Nahkuri et al. 2008). In most species that express HBII-52, clusters of this snoRNA are expressed.

Fig. 21.3 5-HT2C receptor and HBII-52 snoRNA. (a) Small nucleolar RNAs are generated from the SNURF-SNRPN locus. The SNURF-SNRPN gene, located in the Prader-Willi critical region is schematically shown. Exons are shown as boxes, introns as horizontal lines. The bracket labeled SNURF-SNRPN indicates the protein-coding part of the pre-mRNA. Small nucleolar RNAs are located between noncoding exons and are shown as shorter and lighter vertical lines. Their names are indicated on top of the gene structure. A magnification of two snoRNAs (arrows) from the HBII-52 cluster is shown as an enlargement. A thick line with double arrows shows the microdele-tion that causes PWS in one patient (Sahoo et al. 2008). (b) Model for HBII-52 action on the serotonin receptor pre-mRNA. Exon Vb is alternatively spliced. Skipping of the exon leads to a premature stop codon and is predicted to generate a nonfunctional receptor. However, it is not clear whether this nonfunctional protein is formed, since the mRNA is predicted to undergo nonsense mediated decay. Editing of the pre-mRNA promotes exon Vb inclusion but changes the amino acid composition in the second intracellular loop that couples to the G protein. The three positions that are changed by editing are indicated with circles, and the possible amino acids are shown below. The snoRNA promotes inclusion of the exon without editing and leads to a receptor that has the amino acids INI (isoleucine, asparagine, isoleucine) at the positions. This receptor has the strongest agonist response, and its expression is reduced in people with Prader-Willi syndrome

For example, humans posses 47 HBII-52 copies flanked by noncoding exons. The exon-snoRNA-exon structure is arranged in tandem (Fig. 21.3a). Each of the copies exhibits sequence complementarity to exonVb of the Serotonin receptor 2C mRNA. The corresponding mouse MBII-52 snoRNAs are expressed throughout the mouse brain. They are most abundant in hippocampus, but absent in choroid plexus and some thalamic nuclei (Rogelj et al. 2003). The expression of MBII-52 is upregulated during early memory consolidation in the hippocampus (Rogelj et al. 2003). This indicates that snoRNAs could convey a "memory signal."

ExonVb of the serotonin receptor is expressed throughout the brain, but it is mostly absent in the choriod plexus. In contrast, the snoRNA MBII-52 is expressed throughout the brain, but is absent in the choroid plexus, indicating a correlation between HBII-52 expression and exon Vb usage. We therefore analyzed the influence of HBII-52 on 5-HT2CR pre-mRNA processing. In these experiments, the snoRNA and a 5-HT2C receptor splicing reporter were transiently expressed in cell lines. This allowed to analyze the influence of HBII-52 on exon Vb inclusion of reporter. We found that HBII-52 promotes usage of exon Vb. In addition, a transient binding of the snoRNA to the 5 HT2C receptor RNA could be detected by UV crosslink followed by RT-PCR (Kishore and Stamm 2006a). These experiments suggested that the snoRNA HBII-52 can promote inclusion of exon Vb and could be a factor that "overwrites" the splicing silencing element in this exon.

Defeat Drugs and Live Free

Defeat Drugs and Live Free

Being addicted to drugs is a complicated matter condition that's been specified as a disorder that evidences in the obsessional thinking about and utilization of drugs. It's a matter that might continue to get worse and become disastrous and deadly if left untreated.

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