Three additional patients with EED-associated overgrowth: potential mutation hotspots identified?

Spellicy, Catherine J.; Peng, Yunhui; Olewiler, Leah; Cathey, Sara; Rogers, R. Curtis; Johnson, Jacob; Alexov, Emil; Lee, Jennifer A.; Friez, Michael J.; Jones, Julie R.

doi:10.1038/s10038-019-0585-5

Cited by 19 publications

(52 citation statements)

References 35 publications

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“…Polycomb group proteins play a pivotal role in establishing and maintaining gene expression patterns during development, differentiation, and tumorigenesis ( 3 , 5 – 8 ). In this study, we show that EED, a critical mediator of PRC complexes, is required for CNS myelination and myelin repair.…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulation of PRC2 components has been implicated in human developmental disorders, neurological diseases, and cancers ( 7 , 8 , 13 ). Here, we demonstrated that EED deficiency in OPCs causes dysmyelination during CNS development.…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulation of PRC2 components has been implicated in human developmental disorders, neurological diseases, and cancers (7,8,13).…”

Section: Prc2 Is Relevant In Myelinating Diseasesmentioning

confidence: 99%

“…Its dysregulation has been implicated in diseases, including developmental disorders, neurodegenerative diseases, and cancers (7)(8)(9)(10)(11)(12)(13). Loss-of-function mutations in individual PRC2 components, EED, enhancer of zeste homolog 2 (EZH2), or suppressor of zeste 12 protein homolog (SUZ12), can cause human Weaver-like or Cohen-Gibson syndrome, a rare congenital disorder characterized by generalized overgrowth, macrocephaly, and intellectual disability (8)(9)(10). Recent studies indicate that a cohort of patients with Weaver-like syndrome exhibit white matter defects and delayed myelination in the brain (8)(9)(10); however, the functions of PRC2 in the myelination process during central nervous system (CNS) development are poorly defined.…”

Section: Introductionmentioning

confidence: 99%

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EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways

et al. 2020

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Mutations in the polycomb repressive complex 2 (PRC2) can cause Weaver-like syndrome, wherein a patient cohort exhibits abnormal white matter; however, PRC2 functions in CNS myelination and regeneration remain elusive. We show here that H3K27me3, the PRC2 catalytic product, increases during oligodendrocyte maturation. Depletion of embryonic ectoderm development (EED), a core PRC2 subunit, reduces differentiation of oligodendrocyte progenitors (OPCs), and causes an OPC-to-astrocyte fate switch in a region-specific manner. Although dispensable for myelin maintenance, EED is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptomic analyses indicate that EED establishes a chromatin landscape that selectively represses inhibitory WNT and bone morphogenetic protein (BMP) signaling, and senescence-associated programs. Blocking WNT or BMP pathways partially restores differentiation defects in EED-deficient OPCs. Thus, our findings reveal that EED/PRC2 is a crucial epigenetic programmer of CNS myelination and repair, while demonstrating a spatiotemporal-specific role of PRC2-mediated chromatin silencing in shaping oligodendrocyte identity and lineage plasticity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Dysregulation of PRC2 components has been implicated in human developmental disorders, neurological diseases, and cancers (7,8,13).…”

Section: Prc2 Is Relevant In Myelinating Diseasesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways

et al. 2020

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“…Although simple haploinsufficiency is not thought to be the mutational mechanism underlying Weaver syndrome, there is a report of an individual who is haploinsufficient for EZH2 and exhibits some of the features of Weaver syndrome, including overgrowth and intellectual disability (Suri and Dixit, 2017). The overgrowth-associated pathogenic variants of EZH2 , EED and SUZ12 have, to date, been predicted to be caused by predominantly loss-of-function mutations (Cohen et al, 2016; Imagawa et al, 2017; Lui et al, 2018; Spellicy et al, 2019; Tatton-Brown et al, 2013). However, change- or gain-of-function mutations cannot be ruled out in the absence of more thorough biochemical characterisation.…”

Section: A Role For Imbalanced Crosstalk Between Prc2 Nsd1 and Dnmt3mentioning

confidence: 99%

PRC2 functions in development and congenital disorders

Deevy

Bracken

2019

Development

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Polycomb repressive complex 2 (PRC2) is a conserved chromatin regulator that is responsible for the methylation of histone H3 lysine 27 (H3K27). PRC2 is essential for normal development and its loss of function thus results in a range of developmental phenotypes. Here, we review the latest advances in our understanding of mammalian PRC2 activity and present an updated summary of the phenotypes associated with its loss of function in mice. We then discuss recent studies that have highlighted regulatory interplay between the modifications laid down by PRC2 and other chromatin modifiers, including NSD1 and DNMT3A. Finally, we propose a model in which the dysregulation of these modifications at intergenic regions is a shared molecular feature of genetically distinct but highly phenotypically similar overgrowth syndromes in humans.

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Manifestation of epilepsy in a patient with EED‐related overgrowth (Cohen–Gibson syndrome)

Hetzelt

Winterholler²,

Kerling³

et al. 2021

American J of Med Genetics Pt A

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Cohen–Gibson syndrome is a rare genetic disorder, characterized by fetal or early childhood overgrowth and mild to severe intellectual disability. It is caused by heterozygous aberrations in EED, which encodes an evolutionary conserved polycomb group (PcG) protein that forms the polycomb repressive complex‐2 (PRC2) together with EZH2, SUZ12, and RBBP7/4. In total, 11 affected individuals with heterozygous pathogenic variants in EED were reported, so far. All variants affect a few key residues within the EED WD40 repeat domain. By trio exome sequencing, we identified the heterozygous missense variant c.581A > G, p.(Asn194Ser) in exon 6 of the EED‐gene in an individual with moderate intellectual disability, overgrowth, and epilepsy. The same pathogenic variant was detected in 2 of the 11 previously reported cases. Epilepsy, however, was only diagnosed in one other individual with Cohen–Gibson syndrome before. Our findings further confirm that the WD40 repeat domain represents a mutational hotspot; they also expand the clinical spectrum of Cohen–Gibson syndrome and highlight the clinical variability even in individuals with the same pathogenic variant. Furthermore, they indicate a possible association between Cohen–Gibson syndrome and epilepsy.

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Three additional patients with EED-associated overgrowth: potential mutation hotspots identified?

Cited by 19 publications

References 35 publications

EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways

EED-mediated histone methylation is critical for CNS myelination and remyelination by inhibiting WNT, BMP, and senescence pathways

PRC2 functions in development and congenital disorders

Manifestation of epilepsy in a patient with EED‐related overgrowth (Cohen–Gibson syndrome)

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