Deletion of the MBII-85 snoRNA Gene Cluster in Mice Results in Postnatal Growth Retardation

Skryabin, Boris V.; Gubar, Leonid; Seeger, Birte; Pfeiffer, Jana; Handel, Sergej; Robeck, Thomas; Карпова, Е. В.; Rozhdestvensky, Timofey S.; Brosius, Jürgen

doi:10.1371/journal.pgen.0030235

Cited by 163 publications

(165 citation statements)

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“…The deletion encompasses only snoRNAs: HBII-438A, all snoRNAs of the HBII-85 cluster and 23 of the 47 HBII-52 snoRNAs. Since this child shows most clinical features of Prader-Willi syndrome, it is now very clear that the loss of snoRNAs cause the disease [36], which is in agreement with genetic studies and reflected by two recent mouse models [37][38][39]. A possible link between snoRNPs and splice site selection was mechanistically hard to understand, as snoRNPs reside in the nucleolus and splicing takes place in the nucleoplasma.…”

Section: Changes In Alternative Splicing Can Be the Cause Or Consequesupporting

confidence: 62%

“…The low affinity of each interaction is an intrinsic property of pre-mRNA processing and allows the transient formation of a specific protein:RNA complex from several intrinsically weak interactions. This has several advantages: (i) it allows a high sequence flexibility of exonic regulatory sequences that puts no constrains on coding requirements, (ii) the protein interaction can be influenced by small changes in the concentration of regulatory proteins which allows the alternative usage of exons depending on a tissue and/or [37][38][39]. A possible link between snoRNPs and splice site selection was mechanistically hard to understand, as snoRNPs reside in the nucleolus and splicing takes place in the nucleoplasma.…”

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confidence: 99%

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Alternative Splicing and Disease

Jeanteur¹

2006

Progress in Molecular and Subcellular Biology

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Almost all protein-coding genes are spliced and their majority is alternatively spliced. Alternative splicing is a key element in eukaryotic gene expression that increases the coding capacity of the human genome and an increasing number of examples illustrates that the selection of wrong splice sites causes human disease. A fine-tuned balance of factors regulates splice site selection. Here, we discuss well-studied examples that show how a disturbance of this balance can cause human disease. The rapidly emerging knowledge of splicing regulation now allows the development of treatment options. General principles of alternative splicingAlternative pre-mRNA splicing regulates the function of the majority of protein-coding genes An average human protein-coding gene contains a mean of 8.8 exons with a mean size of 145 nt. The mean intron length is 3365 nt and the 5′ and 3′ UTR are 770 and 300 nt, respectively; as a result, this "standard" gene spans about 27 kbp. After pre-mRNA processing the average mRNA exported into the cytosol consists of 1340 nt coding sequence, 1070 nt untranslated regions and a poly (A) tail [1]. This shows that more than 90% of the pre-mRNA is removed as introns, and only about 10% of the average pre-mRNA are joined as exonic sequences by pre-mRNA splicing. Almost all protein-coding genes contain introns that are removed in the nucleus by RNA splicing during pre-mRNA processing. Exon usage is often alternative, i.e. the cell decides whether to remove a part of the pre-mRNA as an intron or include this part in the mature mRNA as an alternative exon [2]; (Figure 1). Alternative pre-mRNA processing is a key regulator of gene expression as it generates numerous transcripts from a single protein-coding gene, which largely increases the use of genetic information. The process is more widely used than previously thought and was recently estimated to affect more than 88% of human protein-coding genes [3]. AnCorrespondence to: Stefan Stamm. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript estimated 75% of alternative exons encode protein parts [4] and their alternate use allows to generate multiple proteins from a single gene, which increases the coding potential of the genome. Mapping of alternatively spliced regions on known protein structures suggest that most alternative exons are in coiled or loop regions that are located on the surface [5]. Alternative splicing generates protein isoforms with different biological properties that differ in protein:protein intera...

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Section: Changes In Alternative Splicing Can Be the Cause Or Consequesupporting

confidence: 62%

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confidence: 99%

Alternative Splicing and Disease

Jeanteur¹

2006

Progress in Molecular and Subcellular Biology

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“…93 Studies with mouse models of PWS also provide support for early starvation theory with neonatal failure to thrive and the later hyperphagic phenotype resultant from a failure of compensatory mechanisms, 94,95 although the latter study did not find problems with placenta of the mice. We have suggested that in PWS patients, fetal starvation may be related to the food intake reducing hormone leptin in the placenta.…”

Section: Pathophysiological Mechanismsmentioning

confidence: 98%

Development of the eating behaviour in Prader–Willi Syndrome: advances in our understanding

2010

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Prader-Willi Syndrome (PWS) is a genetically determined neurodevelopmental disorder associated with mild to moderate intellectual disability, growth and sex-hormone deficiencies and a propensity to overeat that leads to severe obesity. The PWS phenotype changes from an early disinterest in food to an increasing pre-occupation with eating and a failure of the normal satiety response to food intake. The prevention of severe obesity is primarily through strict control of access to food and it is this aspect that most limits the independence of those with PWS. This review considers the eating disorder in PWS, specifically how the as yet uncertain genetics of the syndrome and the transition from the early to the later phenotype might account for the later hyperphagia. On the basis of behavioural and imaging studies, a failure of satiety and excessive activation of neural reward pathways have both been suggested. We speculate that the overeating behaviour, consequent upon one or other of the above, could either be due to a direct effect of the PWS genotype on the feeding pathways of the hypothalamus or a consequence of prenatal changes in the regulation of genes responsible for energy balance that sets a high satiation threshold. Understanding the overeating in PWS will lead to more focused and successful management and ultimately, treatment of this life-threatening behaviour. International Journal of Obesity (2011) IntroductionWe review the present state of knowledge on the eating disorder and potential resultant life-threatening obesity that is associated with Prader-Willi Syndrome (PWS), a genetically determined neurodevelopmental disorder affecting 1 in 22-25 000 live births.1-3 The aims of the review are: first, to consider our understanding of the eating disorder associated with PWS primarily from a behavioural and neuroscience perspective; second, to speculate as to the possible mechanisms that might directly or indirectly link the PWS genotype to the 'eating' phenotype; and third, to reflect on the implications for future research and for treatment. We discuss the major theories that could account for eating behaviour and whether any of these adequately explain the complex array of characteristics that exist in PWS and fit with what we know about the pathophysiology and the genetics of the disorder. The main discussion items include considering PWS as a disorder of satiety, as well as theories of hyper-responsive rewards systems and over-sensitivity to food stimuli, as has been proposed in general obesity. Further, we consider the importance of the prenatal environment and examine the possibility that people with PWS have an altered inner physical awareness, as shown by abnormal pain responses, and how this may alter the eating behaviour. MethodThis review has been carried out through a search of relevant articles primarily on the PubMed search engine (www. pubmed.gov) using 'eating behaviour Prader-Willi syndrome OR Prader Willi syndrome' as the search term. As the eating behaviour is such a key feature of t...

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“…In a further mouse snoRNA knockout, the entire cluster encoding Snord116 RNA isoforms (earlier termed MBII-85 snoRNA) was deleted from a locus associated with Prader-Willi syndrome, a neurodevelopmental disorder in humans. Two independent studies revealed that the mice showed failure to thrive and growth retardation, but not all symptoms described for humans (Skryabin et al 2007;Ding et al 2008). In many multicellular organisms, snoRNAs are cotranscribed with introns of protein-coding genes or nonprotein-coding genes.…”

Section: The (Nucleic) Acid Test For Functionmentioning

confidence: 99%

The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular Function

Brosius

2014

Cold Spring Harbor Perspectives in Biology

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Deletion of the MBII-85 snoRNA Gene Cluster in Mice Results in Postnatal Growth Retardation

Cited by 163 publications

References 39 publications

Alternative Splicing and Disease

Alternative Splicing and Disease

Development of the eating behaviour in Prader–Willi Syndrome: advances in our understanding

The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular Function

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