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American Journal of Medical Genetics.... May 2013NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin...
NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key roles in the regulation of transcription through histone modification and chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone 3 (H3K36) and is primarily associated with active transcription, while EZH2 shows specificity for lysine residue 27 (H3K27) and is associated with transcriptional repression. Somatic dysregulation of NSD1 and EZH2 have been associated with tumorigenesis. NSD1, as a fusion transcript with NUP98, plays a key role in leukemogenesis, particularly childhood acute myeloid leukemia. EZH2 is a major proto-oncogene and mono- and biallelic activating and inactivating somatic mutations occur as early events in the development of tumors, particularly poor prognosis hematopoietic malignancies. Constitutional NSD1 and EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth syndromes with considerable phenotypic overlap. NSD1 mutations that cause Sotos syndrome are loss-of-function, primarily truncating mutations or missense mutations at key residues in functional domains. EZH2 mutations that cause Weaver syndrome are primarily missense variants and the rare truncating mutations reported to date are in the last exon, suggesting that simple haploinsufficiency is unlikely to be generating the overgrowth phenotype although the exact mechanism has not yet been determined. Many additional questions about the molecular and clinical features of NSD1 and EZH2 remain unanswered. However, studies are underway to address these and, as more cases are ascertained and technology improves, it is hoped that these will, in time, be answered.
Topics: Enhancer of Zeste Homolog 2 Protein; Germ-Line Mutation; Growth; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Polycomb Repressive Complex 2; Proto-Oncogene Mas; Proto-Oncogenes
PubMed: 23592277
DOI: 10.1002/ajmg.c.31359 -
Journal of Dairy Science Sep 2016Phenotypes from the August 2015 US national genetic evaluation were used to compute phenotypic effects of 18 recessive haplotypes in Ayrshire (n=1), Brown Swiss (n=5),...
Phenotypes from the August 2015 US national genetic evaluation were used to compute phenotypic effects of 18 recessive haplotypes in Ayrshire (n=1), Brown Swiss (n=5), Holstein (n=10), and Jersey (n=2) cattle on milk, fat, and protein yields, somatic cell score (SCS), single-trait productive life (PL), daughter pregnancy rate (DPR), heifer conception rate (HCR), and cow conception rate (CCR). The haplotypes evaluated were Ayrshire haplotype 1, Brown Swiss haplotypes 1 and 2, spinal dysmyelination, spinal muscular atrophy, Weaver Syndrome, brachyspina, Holstein cholesterol deficiency, Holstein haplotypes 1 to 5, bovine leukocyte adhesion deficiency, complex vertebral malformation, mulefoot (syndactyly), and Jersey haplotypes 1 and 2. When causal variants are unknown and tests are based only on single nucleotide polymorphism haplotypes, it can sometimes be difficult to accurately determine carrier status. For example, 2 Holstein haplotypes for cholesterol deficiency have the same single nucleotide polymorphism genotype, but only one of them carries the causative mutation. Genotyped daughters of carrier bulls included in the analysis ranged from 8 for Weaver Syndrome to 17,869 for Holstein haplotype 3. Lactation records preadjusted for nongenetic factors and direct genomic values (DGV) were used to estimate phenotypic and genetic effects of recessive haplotypes, respectively. We found no phenotypic or genetic differences between carriers and noncarriers of Ayrshire or Brown Swiss defects. Several associations were noted for Holstein haplotypes, including fat and HCR for Holstein haplotype 0 carriers; milk, protein, SCS, PL, and fertility for Holstein haplotype 1; protein, PL, CCR, and HCR for Holstein haplotype 2; milk, protein, and fertility for Holstein haplotype 4; and protein yield and DPR for Holstein haplotype 5. There were no differences among bovine leukocyte adhesion deficiency carriers, but complex vertebral malformation affected fat yield and mulefoot carriers had higher SCS and lower PL DGV. Jersey haplotype 1 was not associated with any phenotypic effects, but we noted significant differences among DGV for fat, protein, PL, DPR, CCR, and HCR. Jersey haplotype 2 was associated only with lower phenotypic CCR. Effects of the recessive haplotypes on other traits studied generally were small even when significant. Almost $11 million of economic losses per year due to reduced fertility and perinatal calf death in the US population can be avoided by selecting mate pairs that will not produce affected embryos. Carrier animals may continue to be selected if the merit of their favorable alleles exceeds the loss from their recessive alleles, but carrier bulls can be generally avoided without reducing the average genetic merit of the sires available for mating.
Topics: Animals; Breeding; Cattle; Cholesterol; Dietary Fats; Female; Fertility; Genomics; Genotyping Techniques; Haplotypes; Lactation; Longevity; Milk; Milk Proteins; Phenotype; Polymorphism, Single Nucleotide; Pregnancy; Pregnancy Rate; Reproduction
PubMed: 27394947
DOI: 10.3168/jds.2015-10777 -
Journal of Medical Genetics Apr 1987A female with the Weaver syndrome is reported. In addition to the characteristic manifestations of overgrowth and advanced bone age, the facies were typical, with a...
A female with the Weaver syndrome is reported. In addition to the characteristic manifestations of overgrowth and advanced bone age, the facies were typical, with a broad forehead, hypertelorism, a long philtrum, micrognathia, and large ears. Like most other patients with Weaver syndrome, she was developmentally delayed, hypertonic, and had a hoarse voice. Other clinical features included prominent finger pads, narrow hyperconvex nails, small and narrow chest, unilateral dislocated distal ulna, and abnormal thoracic vertebrae.
Topics: Abnormalities, Multiple; Age Determination by Skeleton; Bone Diseases, Developmental; Child, Preschool; Face; Female; Humans; Sex; Syndrome
PubMed: 3585940
DOI: 10.1136/jmg.24.4.232 -
American Journal of Human Genetics Jan 2012We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare...
We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare variants in the affected probands against the parental variants identified two different de novo mutations in the enhancer of zeste homolog 2 (EZH2). Sanger sequencing of EZH2 in a third classically-affected proband identified a third de novo mutation in this gene. These data show that mutations in EZH2 cause Weaver syndrome.
Topics: Abnormalities, Multiple; Adolescent; Adult; Base Sequence; Child; Child, Preschool; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA Mutational Analysis; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Exome; Female; Hand Deformities, Congenital; Humans; Infant; Male; Molecular Sequence Data; Mutation; Pedigree; Polycomb Repressive Complex 2; Transcription Factors; Young Adult
PubMed: 22177091
DOI: 10.1016/j.ajhg.2011.11.018 -
BMC Bioinformatics Sep 2022Pathogenic mutations in genes that control chromatin function have been implicated in rare genetic syndromes. These chromatin modifiers exhibit extraordinary diversity...
BACKGROUND
Pathogenic mutations in genes that control chromatin function have been implicated in rare genetic syndromes. These chromatin modifiers exhibit extraordinary diversity in the scale of the epigenetic changes they affect, from single basepair modifications by DNMT1 to whole genome structural changes by PRM1/2. Patterns of DNA methylation are related to a diverse set of epigenetic features across this full range of epigenetic scale, making DNA methylation valuable for mapping regions of general epigenetic dysregulation. However, existing methods are unable to accurately identify regions of differential methylation across this full range of epigenetic scale directly from DNA methylation data.
RESULTS
To address this, we developed DMRscaler, a novel method that uses an iterative windowing procedure to capture regions of differential DNA methylation (DMRs) ranging in size from single basepairs to whole chromosomes. We benchmarked DMRscaler against several DMR callers in simulated and natural data comparing XX and XY peripheral blood samples. DMRscaler was the only method that accurately called DMRs ranging in size from 100 bp to 1 Mb (pearson's r = 0.94) and up to 152 Mb on the X-chromosome. We then analyzed methylation data from rare-disease cohorts that harbor chromatin modifier gene mutations in NSD1, EZH2, and KAT6A where DMRscaler identified novel DMRs spanning gene clusters involved in development.
CONCLUSION
Taken together, our results show DMRscaler is uniquely able to capture the size of DMR features across the full range of epigenetic scale and identify novel, co-regulated regions that drive epigenetic dysregulation in human disease.
Topics: Chromatin; DNA Methylation; Epigenesis, Genetic; Epigenomics; Genome; Humans
PubMed: 36064314
DOI: 10.1186/s12859-022-04899-1 -
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 -
Molecular Cell May 2018PRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its...
PRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its terminal enzymatic product, H3K27me3, is specifically recognized and bound by an aromatic cage present in its EED subunit. The ensuing allosteric activation of the complex stimulates H3K27me3 deposition on chromatin. Here we report a stepwise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found to be mutated in cancers and/or Weaver syndrome. PRC2 harboring these EZH2 or EED mutants manifested little activity in vivo but, unexpectedly, exhibited similar chromatin association as wild-type PRC2, indicating an uncoupling of PRC2 activity and recruitment. With genetic and chemical tools, we demonstrated that targeting allosteric activation overrode the gain-of-function effect of EZH2 oncogenic mutations. These results revealed critical implications for the regulation and biology of PRC2 and a vulnerability in tackling PRC2-addicted cancers.
Topics: Abnormalities, Multiple; Allosteric Regulation; Cell Line, Tumor; Chromatin; Congenital Hypothyroidism; Craniofacial Abnormalities; Enhancer of Zeste Homolog 2 Protein; Hand Deformities, Congenital; Histones; Humans; Neoplasms; Polycomb Repressive Complex 2
PubMed: 29681499
DOI: 10.1016/j.molcel.2018.03.020 -
Human Mutation Mar 2016Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual...
Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, whereas WS-associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2.
Topics: Abnormalities, Multiple; Congenital Hypothyroidism; Craniofacial Abnormalities; Enhancer of Zeste Homolog 2 Protein; Female; Hand Deformities, Congenital; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Infant; Infant, Newborn; Male; Polycomb Repressive Complex 2
PubMed: 26694085
DOI: 10.1002/humu.22946 -
Journal of Medical Genetics Jun 2003Sotos syndrome is an overgrowth syndrome characterised by pre- and postnatal overgrowth, macrocephaly, advanced bone age, and typical facial features. Weaver syndrome is...
Sotos syndrome is an overgrowth syndrome characterised by pre- and postnatal overgrowth, macrocephaly, advanced bone age, and typical facial features. Weaver syndrome is a closely related condition characterised by a distinctive craniofacial appearance, advanced carpal maturation, widened distal long bones, and camptodactyly. Haploinsufficiency of the NSD1 gene has recently been reported as the major cause of Sotos syndrome while point mutations accounted for a minority of cases. We looked for NSD1 deletions or mutations in 39 patients with childhood overgrowth. The series included typical Sotos patients (23/39), Sotos-like patients (lacking one major criteria, 10/39), and Weaver patients (6/39). We identified NSD1 deletions (6/33) and intragenic mutations (16/33) in Sotos syndrome patients. We also identified NSD1 intragenic mutations in 3/6 Weaver patients. We conclude therefore that NSD1 mutations account for most cases of Sotos syndrome and a significant number of Weaver syndrome cases in our series. Interestingly, mental retardation was consistently more severe in patients with NSD1 deletions. Macrocephaly and facial gestalt but not overgrowth and advanced bone age were consistently observed in Sotos syndrome patients. We suggest therefore considering macrocephaly and facial gestalt as mandatory criteria for the diagnosis of Sotos syndrome and overgrowth and advanced bone age as minor criteria.
Topics: Abnormalities, Multiple; Adult; Carrier Proteins; Child; Child, Preschool; Chromosome Deletion; Craniofacial Abnormalities; DNA Mutational Analysis; Developmental Disabilities; Female; Genotype; Growth Disorders; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Intellectual Disability; Intracellular Signaling Peptides and Proteins; Male; Mutation; Nuclear Proteins; Phenotype; Physical Chromosome Mapping; Syndrome
PubMed: 12807965
DOI: 10.1136/jmg.40.6.436 -
Nature Communications Dec 2015Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by...
Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.
Topics: DNA Methylation; Gene Expression Regulation; Genome, Human; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Intracellular Signaling Peptides and Proteins; Mutation; Nuclear Proteins; Sotos Syndrome
PubMed: 26690673
DOI: 10.1038/ncomms10207