2013
DOI: 10.1371/journal.pgen.1003752
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Stochastic Loss of Silencing of the Imprinted Ndn/NDN Allele, in a Mouse Model and Humans with Prader-Willi Syndrome, Has Functional Consequences

Abstract: Genomic imprinting is a process that causes genes to be expressed from one allele only according to parental origin, the other allele being silent. Diseases can arise when the normally active alleles are not expressed. In this context, low level of expression of the normally silent alleles has been considered as genetic noise although such expression has never been further studied. Prader-Willi Syndrome (PWS) is a neurodevelopmental disease involving imprinted genes, including NDN, which are only expressed fro… Show more

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Cited by 32 publications
(33 citation statements)
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References 52 publications
(76 reference statements)
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“…One sample with a diagnosis of autism showed hypomethylation of NDN , whereas a second individual with schizophrenia showed hypomethylation at both NDN and the neighboring imprinted gene MAGEL2 . Aberrant imprinting of NDN has previously been linked with disruption of serotonergic neurons in mice (Rieusset et al, ), and thus it is possible that these imprinting anomalies contribute to the diagnosis of autism and schizophrenia. It should be noted, however, that due to the allele‐specific nature of methylation at imprinted loci, it is possible that the presence of an underlying heterozygous deletion at these regions could be incorrectly interpreted as an epivariation.…”
Section: Discussionmentioning
confidence: 99%
“…One sample with a diagnosis of autism showed hypomethylation of NDN , whereas a second individual with schizophrenia showed hypomethylation at both NDN and the neighboring imprinted gene MAGEL2 . Aberrant imprinting of NDN has previously been linked with disruption of serotonergic neurons in mice (Rieusset et al, ), and thus it is possible that these imprinting anomalies contribute to the diagnosis of autism and schizophrenia. It should be noted, however, that due to the allele‐specific nature of methylation at imprinted loci, it is possible that the presence of an underlying heterozygous deletion at these regions could be incorrectly interpreted as an epivariation.…”
Section: Discussionmentioning
confidence: 99%
“…It is intriguing that a deletion of the entire gene leads to a milder phenotype than a truncating mutation. It is possible that the deletion of the complete paternal copy of the gene and its promoter as seen in the latter cases could lead to the leaky expression of the maternal copy of the MAGEL2 gene, as shown in the recent finding of stochastic loss of silencing of the imprinted Ndn allele in mice (104, 105). Alternatively, MAGEL2 is coded by a single exon and therefore mutations in MAGEL2 likely do not cause nonsense-mediated decay of the mRNA and may result in aberrant truncated protein products with potential dominant negative or other neomorphic effects.…”
Section: Magel2 In Prader-willi and Schaaf-yang Syndromesmentioning
confidence: 99%
“…It is important to note, however, that mouse model systems do not recapitulate the full gamut of behavioral phenotypes exhibited by AS and PWS patients. For example, some, but not all, mice models for PWS exhibit increased appetite, which is also observed in human PWS patients (Rieusset et al, 2013), but this may not be from the lack of satiation that underlies these phenotypes in humans.…”
Section: Fig 2 Imprinting Mechanisms (A) the Insulator Model Is Bestmentioning
confidence: 99%