Prader-Willi and Angelman syndromes: Sister imprinted disorders

University of California, Irvine, USA.
American Journal of Medical Genetics (Impact Factor: 3.23). 02/2000; 97(2):136-46.
Source: PubMed


Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct complex disorders mapped to chromosome 15q11-q13. They both have characteristic neurologic, developmental, and behavioral phenotypes plus other structural and functional abnormalities. However, the cognitive and neurologic impairment is more severe in AS, including seizures and ataxia. The behavioral and endocrine disorders are more severe in PWS, including obsessive-compulsive symptoms and hypothalamic insufficiency. Both disorders can result from microdeletion, uniparental disomy, or an imprinting center defect in 15q11-q13, although the abnormality is on the paternally derived chromosome 15 for PWS and the maternally derived 15 for AS because of genomic imprinting. Although the same gene may control imprinting for both disorders, the gene(s) causing their phenotypes differ. AS results from underexpression of a single gene, UBE3A, which codes for E6-AP, a protein that functions to transfer small ubiquitin molecules to certain target proteins, to enable their degradation. The genes responsible for PWS are not determined, although several maternally imprinted genes in 15q11-q13 are known. The most likely candidate is SNRPN, which codes for a small nuclear ribonucleoprotein, a ribosome-associated protein that controls gene splicing and thus synthesis of critical proteins in the brain. Animal models exist for both disorders. The genetic relationship between PWS and AS makes them unique and potentially highly instructive disorders that contribute substantially to the population burden of cognitive impairment.

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    • "Prader–Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11-q13 (Cassidy et al., 2000). Imprinted genes are those that are epigenetically marked in a parentof-origin-dependent manner during gametogenesis, and consequently expression of these genes in somatic cells is from one parental allele only. "
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    ABSTRACT: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11-q13, the most recognised feature of which is hyperphagia. This is thought to arise as a consequence of abnormalities in both the physiological drive for food and the rewarding properties of food. Although a number of mouse models for PWS exist, the underlying variables dictating maladaptive feeding remain unknown. Here, we characterised feeding behaviour in a mouse model in which the imprinting centre (IC) of the syntenic PWS interval has been deleted (PWS(IC) (del) mice). We demonstrate that PWS(IC) (del) mice show hyperghrelinemia and increased consumption of food both following overnight fasting, and when made more palatable with sucrose. However, hyperphagia in PWS(IC) (del) mice was not accompanied by any changes in reactivity to the hedonic properties of palatable food (sucrose or saccharin), as measured by lick-cluster size. Nevertheless, overall consumption by PWS(IC) (del) mice for non-caloric saccharin in the licking test was significantly reduced. Combined with converging findings from a continuous reinforcement schedule, these data indicate that PWS(IC) (del) mice show a marked heightened sensitivity to the calorific value of food. Overall, these data indicate that any impact of the rewarding properties of food on the hyperphagia seen in PWS(IC) (del) mice is driven by primarily by calorie-content and is unlikely to involve hedonic processes. This has important implications for our understanding of the neural systems underlying the feeding phenotype of PWS and the contribution of imprinted genes to abnormal feeding behaviour more generally. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jun 2015 · European Journal of Neuroscience
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    • "In particular, topoisomerase inhibitors have recently been used to reactivate the silenced paternal Ube3a gene, which encodes a ubiquitin E3 ligase, to compensate for the deleted maternal Ube3a in Angelman syndrome (AS). AS and Prader-Willi syndrome (PWS) are imprinted neurodevelopmental disorders that are often caused by large deletions of human chromosome 15q11–q13 over the Snord116 gene locus, but the deletion differs in its parent-of-origin [100]. In neurons, only the maternal Ube3a allele is expressed, because the paternal Ube3a allele is silenced by expression of the ncRNA Ube3a-ATS (Figure 3A) [101]. "
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    ABSTRACT: R-loops are cellular structures composed of an RNA/DNA hybrid, which is formed when the RNA hybridises to a complementary DNA strand and a displaced single-stranded DNA. R-loops have been detected in various organisms from bacteria to mammals and play crucial roles in regulating gene expression, DNA and histone modifications, immunoglobulin class switch recombination, DNA replication, and genome stability. Recent evidence suggests that R-loops are also involved in molecular mechanisms of neurological diseases and cancer. In addition, mutations in factors implicated in R-loop biology, such as RNase H and SETX (senataxin), lead to devastating human neurodegenerative disorders, highlighting the importance of correctly regulating the level of R-loops in human cells. In this review we summarise current advances in this field, with a particular focus on diseases associated with dysregulation of R-loop structures. We also discuss potential therapeutic approaches for such diseases and highlight future research directions.
    Full-text · Article · Sep 2014 · PLoS Genetics
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    • "Many studies have targeted to the paternally expressed SNORD116 snoRNAs (small nucleolar RNA, C/D box 116 cluster) located within the SNURF/SNRPN locus to have an important role in the PWS aetiology (Ding et al., 2008; Sahoo et al., 2008; de Smith et al., 2009). Moreover, Angelman syndrome (AS), characterized for severe cognitive and neurological disability, results from an underexpression of the maternally imprinted gene UBE3A (encoding for the ubiquitin protein ligase E3A) located also within chromosome 15q11-q13 (Cassidy et al., 2000; Ishida & Moore, 2012). Although the main causes for both syndromes have been attributed to chromosomal deletions, duplications or uniparental disomy, epimutations and DNA methylation defects are present in a frequency of 1–3% (PWS) and 2–4% (AS) (Ishida & Moore, 2012). "
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    ABSTRACT: Sperm cryopreservation is widely used in clinic for insemination, in vitro fertilization and other procedures such as intracytoplasmic sperm injection. The assessment after freezing/thawing of spermatozoa viability, motility and sometimes DNA integrity (mainly using fragmentation assays) has been considered enough to guarantee the safety and effectiveness of the technique. However, it is known that, even when fragmentation is absent, a significant DNA damage could be detected in some genome regions. This is particularly important considering that, during the last years, several studies have pointed out the importance of key paternal genes in early embryo development. In this study, using normozoospermic donors, we present a candidate gene approach in which we quantify the number of lesions produced by freezing/thawing over key genes (PRM1, BIK, FSHB, PEG1/MEST, ADD1, ARNT, UBE3A, SNORD116/PWSAS) using quantitative PCR. Our results demonstrated that the cryopreservation protocol used, which is routinely employed in clinic, produced DNA lesions. The genes studied are differentially affected by the process, and genome regions related to Prader-Willi and Angelman syndromes were among the most damaged: SNORD116/PWSAS (4.56 ± 1.84 lesions/10 kb) and UBE3A (2.22 ± 1.3 lesions/10 kb). To check if vitrification protocols could reduce these lesions, another experiment was carried out studying some of those genes with higher differences in the first study (FSHB, ADD1, ARNT and SNORD116/PWSAS). The number of lesions was not significantly reduced compared to cryopreservation. These results could be relevant for the selection of the most adequate available cryopreservation protocol in terms of the number of lesions that produced over key genes, when no differences with other traditional techniques for DNA assessment could be detected.
    Full-text · Article · Sep 2013 · Andrology
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