Eating behavior, prenatal and postnatal growth in Angelman syndrome

Mertz, Line Granild Bie; Christensen, Rikke; Vogel, Ida; Hertz, Jens Michael; Østergaard, John R.

doi:10.1016/j.ridd.2014.07.025

Cited by 23 publications

(42 citation statements)

References 34 publications

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“…Most studies on Angelman and Dup15q syndromes have been focused on neurodevelopmental deficits and roles of UBE3A in the brain, except the findings that obesity is common with Angelman syndrome . Consistent with the well‐defined adipogenic and steatogenic actions of MLL4, Ube3a+/‐ mice showed enhanced susceptibility to HFD‐induced obesity and fatty liver development through increased adiposity and hepatic steatosis relative to their controls (Fig.…”

Section: Discussionmentioning

confidence: 88%

“…A, Supporting Fig. ), suggest that UBE3A in the liver and fat tissues likely antagonizes the known function of MLL4 in steatogenesis and adipogenesis, respectively, by degrading MLL4 and enhanced MLL4 levels direct the obesity phenotype of Angelman syndrome patients . Ube3a+/‐ mice show a lower motor activity due to altered circadian rhythm but no differences in food intake .…”

Section: Discussionmentioning

confidence: 99%

“…Obesity is common with Angelman syndrome, (28)(29)(30)(31) and Ube3a+/-mice, developed as an animal model for Angelman syndrome, (32) also show obesity due to enhanced adipocity. (33) Obesity is a major risk factor for nonalcoholic fatty liver disease, (34) and indeed Mll4+/-mice are resistant to development of both obesity and hepatic steatosis.…”

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confidence: 99%

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UBE3A Suppresses Overnutrition‐Induced Expression of the Steatosis Target Genes of MLL4 by Degrading MLL4

et al. 2019

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Regulation of the protein stability of epigenetic regulators remains ill-defined despite its potential applicability in epigenetic therapies. The histone H3-lysine 4-methyltransferase MLL4 is an epigenetic transcriptional coactivator that directs overnutrition-induced obesity and fatty liver formation, and Mll4 mice are resistant to both. Here we show that the E3 ubiquitin ligase UBE3A targets MLL4 for degradation thereby suppressing high fat diet (HFD)-induced expression of the hepatic steatosis target genes of MLL4. In contrast to Mll4 mice, Ube3a mice are hypersensitive to HFD-induced obesity and fatty liver development. Ube3a ;Mll4 mice lose this hypersensitivity, supporting roles of increased MLL4 levels in both phenotypes of Ube3a mice. Correspondingly, our comparative studies with wild-type, Ube3a and Ube3a and UBE3A-overexpressing transgenic mouse livers demonstrate inverse-correlation of UBE3A protein levels with MLL4 protein levels, expression of the steatosis target genes of MLL4, and their decoration by H3-lysine 4-monomethylation, a surrogate marker for the epigenetic action of MLL4. Therefore, UBE3A indirectly exerts an epigenetic regulation of obesity and steatosis by degrading MLL4. This UBE3A-MLL4 regulatory axis provides a potential therapeutic venue for treating various MLL4-directed pathogeneses, including obesity and hepatic steatosis. This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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UBE3A Suppresses Overnutrition‐Induced Expression of the Steatosis Target Genes of MLL4 by Degrading MLL4

et al. 2019

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“…Among AS patient categories without large deletions, obesity and hyperphagia are common [56, 57]. These classes differ from large deletion AS cases in having two copies of paternally expressed transcripts that are normally expressed from only one allele (see genomic imprinting section below).…”

Section: Ube3a Deficiency In Angelman Syndromementioning

confidence: 99%

Epigenetic Regulation of UBE3A and Roles in Human Neurodevelopmental Disorders

2015

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Summary The E3 ubiquitin ligase protein UBE3A, also known as E6-AP, has a multitude of ascribed functions and targets relevant to human health and disease. Epigenetic regulation of the UBE3A gene by parentally imprinted noncoding transcription within human chromosome 15q11.2-q13.3 is responsible for the maternal-specific effects of 15q11.2-q13.3 deletion or duplication disorders. Here, we review the evidence for diverse and emerging roles for UBE3A in the proteasome, synapse, and nucleus in regulating protein stability and transcription as well as the current mechanistic understanding of UBE3A imprinting in neurons. Angelman and Dup15q syndromes as well as experimental models of these neurodevelopmental disorders are highlighted as improving understanding of UBE3A and its complex regulation for improving therapeutic strategies.

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“…This may be explained by the larger size of genetic defect in patients than that of the AS mice. Further observations on the variations in eating behavior and body growth among patients with different genetic deficits, specifically patients with big deletion or ones with UPD implied that other factors within the 15q11-13 locus may play a role in the pathogenesis too [36,66]. 6.…”

Section: Outstanding Questions and Major Challengesmentioning

confidence: 99%