Home
This Title All WIREs
WIREs RSS Feed
How to cite this WIREs title:
WIREs RNA
Impact Factor: 4.928

Box C/D small nucleolar RNA genes and the Prader‐Willi syndrome: a complex interplay

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

The nucleolus of mammalian cells contains hundreds of box C/D small nucleolar RNAs (SNORDs). Through their ability to base pair with ribosomal RNA precursors, most play important roles in the synthesis and/or activity of ribosomes, either by guiding sequence‐specific 2′‐O‐methylations or by facilitating RNA folding and cleavages. A growing number of SNORD genes with elusive functions have been discovered recently. Intriguingly, the vast majority of them are located in two large, imprinted gene clusters at human chromosome region 15q11q13 (the SNURF–SNRPN domain) and at 14q32 (the DLK1–DIO3 domain) where they are expressed, respectively, only from the paternally and maternally inherited alleles. These placental mammal‐specific SNORD genes have many features of the canonical SNORDs that guide 2′‐O‐methylations, yet they lack obvious complementarity with ribosomal RNAs and, surprisingly, they are processed from large, tandemly repeated genes expressed preferentially in the brain. This review summarizes our understanding of the biology of these peculiar SNORD genes, focusing particularly on SNORD115 and SNORD116 in the SNURF–SNRPN domain. It examines the growing evidence that altered levels of these SNORDs and/or their host‐gene transcripts may be a primary cause of Prader‐Willi syndrome (PWS; a rare disorder characterized by overeating and obesity) as well as abnormalities in signaling through the 5‐HT2C serotonin receptor. Finally, the hypothesis that PWS may be a ribosomopathy (ribosomal disease) is also discussed. WIREs RNA 2017, 8:e1417. doi: 10.1002/wrna.1417 This article is categorized under: Translation > Ribosome Biogenesis RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease
The imprinted SNURF‐SNRPN (PWS) chromosomal domain. (a) The domain at human chromosomal region 15q11q13. (b) The orthologous region on mouse chromosome 7C. The paternally inherited chromosome is shown above and the maternally inherited chromosome below. Alleles expressed from the paternally inherited chromosomes are in blue; those expressed from maternally inherited chromosomes are in pink. Silent alleles are gray and non‐imprinted gene loci are in black. The differentially methylated region imposing the mono‐allelic expression of all imprinted genes over the entire domain (the imprinting center region, ICR) is indicated by filled and open lollipops (methylated and unmethylated, respectively). The SNORD (ovals) gene array is highlighted by the green box; yellow boxes denote gene loci that are not conserved between mouse and human. Dashed lines symbolize the possibility that SNORDs derive from a single, large transcript referred to as Lcnat and U‐UBE3A‐ATS (or IC‐SNURF‐SNRPN) in mouse and human, respectively. PWS‐encoded SNORD genes are embedded within introns of non‐coding transcripts (not shown). In mouse, Snord116 and Snord115 are embedded within regularly spaced repeat units composed of introns flanked by A‐ and G1‐G2‐exons, respectively. These repeat units are not conserved in human. Note that the imprinting of the UBE3A/Ube3a gene is restricted to neurons and that human ATP10A gene shows variable, gender‐specific mono‐allelic expression in the brain. Schematic is not to scale.
[ Normal View | Magnified View ]
Intron‐encoded SNORDs direct sequence‐specific 2′‐O‐methylation of rRNA precursors and U6 snRNA. (a) Biogenesis and function of intron‐encoded SNORD. In mammals, most SNORDs (green rectangle) are encoded within the introns of host genes (SNORD‐HG) and are transcribed by RNA Pol‐II polymerases. Upon splicing, the debranched, linearized intron binds SNORD‐associated proteins and also very likely transiently‐associated SNORD biogenesis factors. This nucleoprotein assembly is believed to impede the progress of 5′ and 3′ exonucleases, thus defining the mature 5′ and 3′ ends of the SNORDs that fold into a K‐turn motif (as in b). The mature snoRNPs can also transit throughout Cajal bodies before accumulating in the nucleoli where they target rRNA precursors and U6 snRNA for 2′‐O‐methylations. (b) Left: consensus K‐turn motif. As illustrated for SNORD115 (middle) and SNORD116 (right), the terminal 5′3′ stem structure shared by most SNORDS form part of the K‐turn motif. (C) and (D) Boxes are written in green; the terminal 5′‐3′ stem is denoted in brown. (c) The ‘fifth nucleotide’ rule. The SNORD (green) contains a ~12–20 nt antisense element (blue) and forms a perfect RNA duplex with its target sequence in rRNA, U6 snRNA or also possibly other cellular RNAs; the nucleotide paired with the fifth residue (red) upstream of the D (or D′) box is 2′‐O‐methylated by the snoRNP‐associated 2′‐O‐methyltransferase, Fibrillarin.
[ Normal View | Magnified View ]
Is PWS a novel example of ribosomal disease? Loss of PWS‐encoded SNORD genes, particularly SNORD116, may cause abnormalities in the synthesis and/or the function of ribosomes in neuronal tissues, possibly during a narrow developmental window. These deficiencies could impact on the fidelity and/or efficiency of translation which, in turn, may contribute, at least in part, to some aspects of the behavioral and/or metabolic abnormalities of PWS.
[ Normal View | Magnified View ]
Genetic and epigenetic abnormalities in PWS. PWS results from deficiencies in the expression of one or several paternally expressed genes (symbolized by red arrow) that map to the imprinted chromosomal region 15q11q13 (brown rectangle). The syndrome can be due to large, de novo deletions of paternal origin (~70%), to inheritance of two silent maternal chromosomes 15 (matUPD15; ~25%) or to rare epigenetic alterations or genetic abnormalities (<5%; red star).
[ Normal View | Magnified View ]
Post‐transcriptional processing of the 5‐HT2C pre‐mRNA. (a) Top: Sequence complementarity in SNORD115 potentially allows it to base‐pair with a functionally important segment of the pre‐mRNA encoding the serotonin receptor variant 5‐HT2C. This pre‐mRNA undergoes alternative RNA splicing at exon V (the alternative and regular donor splice sites are indicated in red and blue, respectively) and ADAR‐mediated A‐to‐I RNA editing at five closely spaced adenosine residues (the A, B, C, D, and E editing sites indicated in green). Note that the nucleotide predicted to be 2′‐O‐methylated by SNORD115 corresponds precisely to editing site C (highlighted in yellow). Bottom: SNORD base‐pairing and/or the resulting 2′‐O‐methylation of the 5‐HT2C pre‐mRNA are believed to improve use of the regular 5′ splice site (right) and/or modulate RNA editing, notably at the C‐site (left). (b) Because inosine is recognized by ribosomes as guanosine, A‐to‐I RNA editing can alter the genetic information encoded in the mRNA. Left: Combinatorial RNA editing events might generate up to 32 mRNA variants encoding 24 different 5‐HT2C receptor isoforms. Right: RNA editing causes three amino‐acid residue changes within the second intracellular loop of the receptor that play pivotal roles in G protein coupling. A receptor produced by a fully edited (VGV) mRNA had reduced constitutive activity, decreased G protein coupling efficacy and decreased serotonin potency when compared to that of produced by an unedited (INI) mRNA.
[ Normal View | Magnified View ]
The SNORD gene array at the imprinted SNURF‐SNRPN domain generates a great diversity of noncoding transcripts. Predicted molecular functions associated with SNORD gene arrays including fully processed SNORDs, spliced Host‐gene (HG), partially‐processed SNORD‐containing RNAs (sno‐lncRNAs and SPA‐lncRNAs), IPW lncRNA and anti‐UBE3A transcripts are summarized in yellow boxes (see text for further details). The imprinted DLK1‐DIO3 domain at 14q32 also contains numerous maternally expressed SNORD genes (SNORD112, SNORD113, and SNORD114) whose tandemly repeated gene organization resembles that of the PWS domain. This 14q32 domain also hosts many miRNA genes (arrow heads), most of them organized as two clusters: the miR‐127/miR‐136 and the miR‐379/miR‐410 clusters. For other symbols, see the legend to Figure . Note that another interaction between the Dlk1–Dio3 and Snurf‐Snrpn regions was recently reported in rat neurons: an alternative Ube3a transcript (Ube3a‐1) functions as a competing endogenous RNA to sequester miR‐134 produced from the miR‐379/miR‐410 cluster. This, in turn, influences activity‐dependent neuronal development.
[ Normal View | Magnified View ]
Evidence that loss of SNORD116 gene array expression causes Prader‐Willi syndrome. (a) The imprinted SNURF‐SNRPN gene cluster at human chromosomal region 15q11q13. The horizontal red bars indicate rare, small deletions of paternal origin that cause PWS; green bars indicate paternal deletions that cause no obvious PWS phenotype. The minimal critical region suspected to contain one or more gene(s) whose deficiencies may cause PWS is indicated by the yellow box. Individuals with a truncated MAGEL2 gene (red star) display Schaaf‐Yang syndrome which resembles PWS. Note that SNORD115 genes are not located within the minimal critical region. (b) The imprinted Snurf‐Snrpn gene cluster at mouse chromosome 7C. The horizontal bars represent deletions generated in PWS mouse models. Red bar: PWS‐like phenotype including growth retardation and hyperphagia. Green bar: no obvious phenotype. Black bars: failure to thrive and 80–100% neonatal lethality. Targeted gene deletions disrupting a single protein‐coding gene are indicated by red stars (associated with some PWS‐related phenotypes) and gray stars (no obvious phenotype). For other symbols, see the legend to Figure .
[ Normal View | Magnified View ]

Browse by Topic

Translation > Ribosome Biogenesis
RNA in Disease and Development > RNA in Disease
RNA Processing > RNA Editing and Modification

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts