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Operative Neurosurgery (Hagerstown, Md.) Aug 2021Deep brain stimulation of the posteromedial hypothalamus (PMH DBS) appears to be an effective treatment for drug-resistant aggressiveness. Weaver syndrome (WS) is a rare... (Review)
Review
BACKGROUND AND IMPORTANCE
Deep brain stimulation of the posteromedial hypothalamus (PMH DBS) appears to be an effective treatment for drug-resistant aggressiveness. Weaver syndrome (WS) is a rare genetic disorder in which patients develop some degree of intellectual disability and rarely severe behavioral alterations that may benefit from this procedure.
CLINICAL PRESENTATION
We present the case of a 26-yr-old man diagnosed with WS presenting with uncontrollable self and heteroaggressiveness and disruptive behavior refractory to pharmacological treatment and under severe physical and mechanical restraining measures. The patient was successfully treated with bilateral PMH DBS resulting in affective improvement, greater tolerance for signs of affection, regularization in his sleep pattern and appetite disturbances at 12-mo follow-up. A detailed description and video of the procedure are presented, and a review of the clinical characteristics of WS and the utility and benefits of PMH DBS for refractory aggressiveness are reviewed.
CONCLUSION
To our knowledge, this is the first case of refractory aggressiveness described in WS as well as the first patient with WS successfully treated with PMH DBS.
Topics: Abnormalities, Multiple; Aggression; Congenital Hypothyroidism; Craniofacial Abnormalities; Deep Brain Stimulation; Hand Deformities, Congenital; Humans; Hypothalamus; Male
PubMed: 34017998
DOI: 10.1093/ons/opab149 -
American Journal of Medical Genetics.... Jul 2021
Topics: Abnormalities, Multiple; Adolescent; Child; Congenital Hypothyroidism; Craniofacial Abnormalities; Enhancer of Zeste Homolog 2 Protein; Fingers; Hand Deformities, Congenital; Humans; Male; Polydactyly; Toes
PubMed: 33788986
DOI: 10.1002/ajmg.a.62189 -
Current Opinion in Structural Biology Apr 2021The polycomb repressive complex 2 (PRC2) is a conserved multiprotein, repressive chromatin complex essential for development and maintenance of eukaryotic cellular... (Review)
Review
The polycomb repressive complex 2 (PRC2) is a conserved multiprotein, repressive chromatin complex essential for development and maintenance of eukaryotic cellular identity. PRC2 comprises a trimeric core of SUZ12, EED and EZH1/2, which together with RBBP4/7 is sufficient to catalyse mono-methylation, di-methylation and tri-methylation of histone H3 at lysine 27 (H3K27me1/2/3). These histone methyltransferase activities of PRC2 are deregulated in several human cancers and certain developmental disorders, such as Weaver Syndrome. Core PRC2 associates with several accessory proteins, which organise to define two main subassemblies, PRC2.1 and PRC2.2. Here we review new biochemical and structural studies that are providing critical insights into how core and accessory PRC2 subunits coordinate the faithful deposition of H3K27 methylations genome-wide.
Topics: Chromatin; Histones; Humans; Methylation; Polycomb Repressive Complex 2; Protein Processing, Post-Translational
PubMed: 33232890
DOI: 10.1016/j.sbi.2020.10.017 -
Molecular Cell Nov 2020Diffuse midline gliomas and posterior fossa type A ependymomas contain the recurrent histone H3 lysine 27 (H3 K27M) mutation and express the H3 K27M-mimic EZHIP...
Diffuse midline gliomas and posterior fossa type A ependymomas contain the recurrent histone H3 lysine 27 (H3 K27M) mutation and express the H3 K27M-mimic EZHIP (CXorf67), respectively. H3 K27M and EZHIP are competitive inhibitors of Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase activity. In vivo, these proteins reduce overall H3 lysine 27 trimethylation (H3K27me3) levels; however, residual peaks of H3K27me3 remain at CpG islands (CGIs) through an unknown mechanism. Here, we report that EZHIP and H3 K27M preferentially interact with PRC2 that is allosterically activated by H3K27me3 at CGIs and impede its spreading. Moreover, H3 K27M oncohistones reduce H3K27me3 in trans, independent of their incorporation into the chromatin. Although EZHIP is not found outside placental mammals, expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved mechanism. Our results provide mechanistic insights for the retention of residual H3K27me3 in tumors driven by H3 K27M and EZHIP.
Topics: Allosteric Regulation; Animals; Chromatin; CpG Islands; DNA Methylation; Drosophila melanogaster; Gene Expression Regulation, Neoplastic; Histones; Humans; Mice; Mutation; Oncogene Proteins; Polycomb Repressive Complex 2
PubMed: 33049227
DOI: 10.1016/j.molcel.2020.09.028 -
Frontiers in Cell and Developmental... 2020Usually overlooked by physicians, olfactory abnormalities are not uncommon. Olfactory malformations have recently been reported in an emerging group of genetic disorders...
Usually overlooked by physicians, olfactory abnormalities are not uncommon. Olfactory malformations have recently been reported in an emerging group of genetic disorders called Mendelian Disorders of the Epigenetic Machinery (MDEM). This study aims to determine the prevalence of olfactory malformations in a heterogeneous group of subjects with MDEM. We reviewed the clinical data of 35 patients, 20 females and 15 males, with a mean age of 9.52 years (SD 4.99). All patients had a MDEM and an already available high-resolution brain MRI scan. Two experienced neuroradiologists reviewed the MR images, noting abnormalities and classifying olfactory malformations. Main findings included Corpus Callosum, Cerebellar vermis, and olfactory defects. The latter were found in 11/35 cases (31.4%), of which 7/11 had Rubinstein-Taybi syndrome (RSTS), 2/11 had CHARGE syndrome, 1/11 had Kleefstra syndrome (KLFS), and 1/11 had Weaver syndrome (WVS). The irregularities mainly concerned the olfactory bulbs and were bilateral in 9/11 patients. With over 30% of our sample having an olfactory malformation, this study reveals a possible new diagnostic marker for MDEM and links the epigenetic machinery to the development of the olfactory bulbs.
PubMed: 32850830
DOI: 10.3389/fcell.2020.00710 -
American Journal of Human Genetics May 2020Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core...
Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Cohort Studies; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA Methylation; Enhancer of Zeste Homolog 2 Protein; Female; Hand Deformities, Congenital; Humans; Infant; Intellectual Disability; Male; Mosaicism; Mutation; Mutation, Missense; Neoplasm Proteins; Polycomb Repressive Complex 2; Reproducibility of Results; Transcription Factors; Young Adult
PubMed: 32243864
DOI: 10.1016/j.ajhg.2020.03.008 -
American Journal of Medical Genetics.... Dec 2019The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component...
The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like phenotype with a rare coding SUZ12 variant-the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver-like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre- and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly-affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically-recognizable syndromes emerge from different variant subtypes.
Topics: Child; Child, Preschool; Female; Growth Disorders; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Mutation; Neoplasm Proteins; Phenotype; Polycomb Repressive Complex 2; Transcription Factors
PubMed: 31736240
DOI: 10.1002/ajmg.c.31748 -
American Journal of Medical Genetics.... Dec 2019The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic "writer" with H3K27... (Review)
Review
The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic "writer" with H3K27 methyltransferase activity, catalyzing the addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss-of-function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2-associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590). EED-associated overgrowth (Cohen-Gibson syndrome; OMIM #617561) is caused by germline heterozygous mutations in Embryonic Ectoderm Development (EED), and manifests overgrowth and intellectual disability (OGID), along with other features similar to Weaver syndrome. Most recently, rare coding variants in SUZ12 have also been described that present with clinical characteristics similar to the previous two syndromes. Here we review the PRC2 complex and clinical syndromes of OGID associated with core components EZH2, EED, and SUZ12.
Topics: Enhancer of Zeste Homolog 2 Protein; Growth Disorders; Humans; Neoplasm Proteins; Phenotype; Polycomb Repressive Complex 2; Syndrome; Transcription Factors
PubMed: 31724824
DOI: 10.1002/ajmg.c.31754 -
Development (Cambridge, England) Oct 2019Polycomb 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... (Review)
Review
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.
Topics: Animals; Congenital Abnormalities; Embryonic Development; Humans; Mammals; Models, Biological; Polycomb Repressive Complex 2; Signal Transduction
PubMed: 31575610
DOI: 10.1242/dev.181354 -
Proceedings of the National Academy of... Apr 2019Enhancer of Zeste Homolog (EZH2) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes monomethylation, dimethylation, and...
Enhancer of Zeste Homolog (EZH2) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes monomethylation, dimethylation, and trimethylation of lysine 27 on histone H3 (H3K27). Trimethylation at H3K27 (H3K27me3) is associated with transcriptional silencing of developmentally important genes. Intriguingly, H3K27me3 is mutually exclusive with H3K36 trimethylation on the same histone tail. Disruptions in this cross-talk result in aberrant H3K27/H3K36 methylation patterns and altered transcriptional profiles that have been implicated in tumorigenesis and other disease states. Despite their importance, the molecular details of how PRC2 "senses" H3K36 methylation are unclear. We demonstrate that PRC2 is activated in by the unmodified side chain of H3K36, and that this activation results in a fivefold increase in the of its enzymatic activity catalyzing H3K27 methylation compared with activity on a substrate methylated at H3K36. Using a photo-cross-linking MS strategy and histone methyltransferase activity assays on PRC2 mutants, we find that EZH2 contains a specific sensing pocket for the H3K36 methylation state that allows the complex to distinguish between modified and unmodified H3K36 residues, altering enzymatic activity accordingly to preferentially methylate the unmodified nucleosome substrate. We also present evidence that this process may be disrupted in some cases of Weaver syndrome.
Topics: Binding Sites; Enhancer of Zeste Homolog 2 Protein; Histones; Humans; Models, Molecular; Mutation; Protein Binding; Recombinant Proteins
PubMed: 30967505
DOI: 10.1073/pnas.1819029116