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44-568: Although most cases of Sotos syndrome occur sporadically, familial cases have also been reported. It is similar to Weaver syndrome . This syndrome is characterized by overgrowth and advanced bone age. Affected individuals have dysmorphic features, with macrodolichocephaly , downslanting palpebral fissures and a pointed chin. The facial appearance is most notable in early childhood. Affected infants and children tend to grow quickly; they are significantly taller than their siblings and peers, and have an unusually large skull and large head. Adult height

88-415: A clinically relevant mutation of residue tyrosine 641 to phenylalanine (Y641F) results in higher H3K27 tri-methylation activity. It is proposed that the removal of the hydroxyl group on Y641 abrogates steric hindrance and allows for accommodation of a third methyl group on the substrate lysine. EZH2 is an attractive target for anti-cancer therapy because it helps cancerous cells divide and proliferate. It

132-596: A complex with at least two other PRC2 components, SUZ12 and EED . As a histone methyltransferase (HMTase), EZH2's primary function is to methylate Lys-27 on histone 3 (H3K27me) by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM). EZH2 is capable of mono-, di-, and tri- methylation of H3K27 and has been associated with a variety of biological functions, including transcriptional regulation in hematopoiesis , development, and cell differentiation . EZH2 has also been identified as capable of methylating non- histone proteins. EZH2, as

176-536: A decrease in EZH2 activity. Phosphorylation of T492 has been suggested to disrupt contacts between human EZH2 and its binding partners in the PRC2 complex, thus hindering its catalytic activity. In addition to phosphorylation, it has also been shown that PRC2/EZH2-EED activity is antagonized by transcription-activating histone marks, such as acetylation of H3K27 ( H3K27ac ) and methylation of H3K36 ( H3K36me ). EZH2 expression

220-563: A monotone voice. Additionally, weak muscle tone (hypotonia) may delay other aspects of early development, particularly motor skills such as sitting and crawling. Other signs include scoliosis , seizures, heart or kidney defects, hearing loss, and problems with vision. Some infants with this disorder experience jaundice and poor feeding. A small number of patients with Sotos syndrome have developed cancer, most often in childhood, but no single form of cancer has been associated with this condition. It remains uncertain whether Sotos syndrome increases

264-409: A part of PRC2, catalyzes trimethylation of H3K27 ( H3K27me3 ), which is a histone modification that has been characterized as part of the histone code . The histone code is the theory that chemical modifications, such as methylation , acetylation , and ubiquitination , of histone proteins play distinctive roles in epigenetic regulation of gene transcription . EZH2-mediated catalysis of H3K27me3

308-513: A prominent chin crease, increased prenatal growth, and a carpal bone age that is greatly advanced compared to metacarpal and phalangeal bone age. There is no cure available for Weaver syndrome. However, with multidisciplinary management, such as neurological, pediatric, orthopedic and psychomotor care and genetic counseling, symptoms can be managed. Surgery may be used to correct any skeletal issues. Physical and occupational therapy are considered an option to help with muscle tone. Also, speech therapy

352-629: A rare disorder characterized by advanced bone age, macrocephaly , and hypertelorism . The histidine residue in the active site of the wild-type EZH2 was mutated to tyrosine in patients diagnosed with Weaver syndrome. The mutation likely interferes with cofactor binding and causes disruption of the natural function of the protein. Enhancer of zeste (E(z)) was originally identified in Drosophila melanogaster , and its mammalian homologs were subsequently identified and named EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2). EZH2

396-613: A role in activation of transcription, independently of PRC2 . In breast cancer cells, EZH2 has been demonstrated to activate NF-κB target genes, which are involved in responses to stimuli. The functional role of this activity and its mechanism are still unknown. EZH2 plays an essential role in development. In particular, it helps control transcriptional repression of genes that regulate cell differentiation. In embryonic stem cells, EZH2-mediated trimethylation of H3K27me3 in regions containing developmental genes appears to be important for maintenance of normal cell differentiation. H3K27me3

440-405: A study performed by Zhaomei Mu and his associates concluded that the knockdown gene for EZH2 inhibited both the migration and invasion of IBC cells. Also in vivo , its knockdown gene suppressed tumor growth, most likely by the presence of fewer blood vessels, or reduced angiogenesis, in the EZH2 knockdown tumor versus EZH2 tumors. Mutations in the EZH2 gene have been linked with Weaver syndrome ,

484-470: Is a histone-lysine N-methyltransferase enzyme ( EC 2.1.1.43 ) encoded by EZH2 gene , that participates in histone methylation and, ultimately, transcriptional repression . EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine . Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2

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528-782: Is a viable area of cancer research. EZH2 inhibitor development has focused on targeting the SET domain active site of the protein. Several inhibitors of EZH2 have been developed as of 2015, including 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, and UNC1999. Combination therapies are being studied as possible treatments when primary treatments begin to fail. Etoposide , a topoisomerase inhibitor, when combined with an EZH2 inhibitor, becomes more effective for non-small cell lung cancers with BRG1 and EGFR mutations. However, EZH2 and lysine methylation can have tumor suppressing activity, for example in myelodysplastic syndrome , indicating that EZH2 inhibition may not be beneficial in all cases. EZH2

572-493: Is also important in driving X-inactivation , the silencing of one X-chromosome in females during development. During X-inactivation, it is thought that EZH2 is involved in initiating heterochromatin formation by trimethylating H3K27 and that other histone methyltransferases and histone marks may be involved in maintaining the silenced state. Further, EZH2 has been identified as an essential protein involved in development and differentiation of B-cells and T-cells . H3K27me3

616-801: Is also required during cell mitosis. EZH2 is the functional enzymatic component of the Polycomb Repressive Complex 2 ( PRC2 ), which is responsible for healthy embryonic development through the epigenetic maintenance of genes responsible for regulating development and differentiation . EZH2 is responsible for the methylation activity of PRC2, and the complex also contains proteins required for optimal function ( EED , SUZ12 , JARID2 , AEBP2 , RbAp46/48 , and PCL ). Mutation or over-expression of EZH2 has been linked to many forms of cancer. EZH2 inhibits genes responsible for suppressing tumor development, and blocking EZH2 activity may slow tumor growth. EZH2 has been targeted for inhibition because it

660-416: Is approximately 1 in 14,000 births. Weaver syndrome Weaver syndrome is an extremely rare autosomal dominant genetic disorder associated with rapid growth beginning in the prenatal period and continuing through the toddler and youth years. It is characterized by advanced osseous maturation and distinctive craniofacial, skeletal and neurological abnormalities. It is similar to Sotos syndrome and

704-436: Is associated with long term transcription repression. EZH2, as well as other Polycomb group proteins, are involved in establishing and maintaining gene repression through cell division . This transcriptionally repressive state is thought to be due to PRC2/EZH2-EED-mediated H3K27 methylation and subsequent recruitment of PRC1 which facilitates condensation of chromatin and formation of heterochromatin . Heterochromatin

748-531: Is based on physical examination, looking for excessive growth among other symptoms. There are no biochemical markers for the disease. Treatment is symptomatic . There is no standard course of treatment for Sotos syndrome. Sotos syndrome is not a life-threatening disorder and patients may have a normal life expectancy. Developmental delays may improve in the school-age years; however, coordination problems may persist into adulthood, along with any learning disabilities and/or other physical or mental issues. Incidence

792-568: Is classified as an overgrowth syndrome . Its genetic cause was identified in 2011 as mutations in the EZH2 gene. Forty-eight cases had been documented and confirmed as of December 2013 , and its prevalence is estimated to be similar to that of Sotos syndrome, around 1 in 15,000. It was first described by American physician David Weaver in 1974. Children with Weaver syndrome tend to look similar and have distinctive physical and craniofacial characteristics, which may include several, but not all, of

836-460: Is crucial for epigenetic regulation of specific patterning during osteochondrogenesis, or bone and cartilage development, of the craniofacial skeletal elements. By repressing inhibitors, EZH2 promotes bone and cartilage formation in facial skeletal features arising from the neural crest. Above average EZH2 expression has become a biological marker for the most aggressive form for breast cancer known as Inflammatory Breast Cancer (IBC). But in 2013,

880-477: Is found in larger amounts than in healthy cells in a wide range of cancers including breast, prostate, bladder, uterine , and renal cancers, as well as melanoma and lymphoma . EZH2 is a gene suppressor, so when it becomes overexpressed, many tumor suppressor genes that are normally turned on, are turned off. Inhibition of EZH2 function shrinks malignant tumors in some reported cases because those tumor suppressor genes are not silenced by EZH2. EZH2 typically

924-465: Is highly upregulated. Methylation is the addition of a -CH 3 , or methyl group, to another molecule. In biology, methylation is typically catalyzed by enzymes, and methyl groups are commonly added to either proteins or nucleic acids. In EZH2-catalyzed methylation, the amino acid lysine in the histone h3 is methylated. This amino acid residue can be methylated up to three times on its terminal ammonium group. These methylated lysines are important in

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968-460: Is involved in suppressing genes that promote differentiation, thus maintaining an undifferentiated state of B- and T-cells and playing an important role in regulating hematopoiesis . The activity of EZH2 is regulated by the post-translational phosphorylation of threonine and serine residues on EZH2. Specifically, phosphorylation of T350 has been linked to an increase in EZH2 activity while phosphorylation of T492 and S21 have been linked to

1012-408: Is not expressed in healthy adults; it is only found in actively dividing cells, like those active during fetal development. Because of this characteristic, overexpression of EZH2 can be used as a diagnostic marker of cancer and some neurodegenerative disorders. However, there are cases where it is difficult to tell whether overexpression of EZH2 is the cause of a disease, or simply a consequence. If it

1056-500: Is often recommended for speech related problems. With appropriate treatment and management, patients with Weaver syndrome appear to do well, both physically and intellectually, throughout their life and have a normal lifespan. Their adult height can reach 7–8 feet (213.36–243.84 cm). The incidence of Weaver syndrome is uncertain, as the causative mutation was only identified in 2011. As of December 2013 , 48 cases of Weaver syndrome had been documented and confirmed. In 2012,

1100-423: Is only a consequence, targeting EZH2 for inhibition may not cure the disease. One example of a cancer pathway in which EZH2 plays a role is the pRB-E2F pathway. It is downstream from the pRB-E2F pathway, and signals from this pathway lead to EZH2 overexpression. Another important characteristic of EZH2 is that when EZH2 is overexpressed, it can activate genes without forming PRC2 . This is an issue because it means

1144-600: Is regulated by estrogen signaling in human normal breast epithelium and human breast cancers. EZH2 function is highly dependent upon its recruitment by the PRC2 complex. In particular, WD40-repeat protein embryonic ectoderm development (EED) and zinc finger protein suppressor of zeste 12 (SUZ12) are needed to stabilize the interaction of EZH2 with its histone substrate Recently, two isoforms of EZH2 generated from alternative splicing have been identified in humans: EZH2α and EZH2β. Both isoforms contain elements that have been identified as important for EZH2 function including

1188-644: Is tightly packed chromatin which limits the accessibility of transcription machinery to the underlying DNA, thereby suppressing transcription. During cell division, heterochromatin formation is required for proper chromosome segregation . PRC2/EED-EZH2 complex may also be involved in the recruitment of DNA methyltransferases ( DNMTs ), which results in increased DNA methylation , another epigenetic layer of transcription repression. Specific genes that have been identified as targets of EZH2-mediated transcriptional repression include HOXA9 , HOXC8 , MYT1 , CDKN2A and retinoic acid target genes. In cancer, EZH2 may play

1232-546: Is upregulated in multiple cancers including, but not limited to, breast, prostate , melanoma , and bladder cancer. Mutations in the EZH2 gene are also associated with Weaver syndrome , a rare congenital disorder, and EZH2 is involved in causing neurodegenerative symptoms in the nervous system disorder, ataxia telangiectasia . EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). EZH2's catalytic activity relies on its formation of

1276-639: Is usually in the normal range, although Broc Brown has the condition and was named the world's tallest teenager; as of late 2016, he was 2.34 m (7 ft 8 in) tall and still growing. Individuals with Sotos syndrome often have intellectual impairment, and most also display autistic traits. Frequent behavioral impairments include attention deficit hyperactivity disorder (ADHD), phobias , obsessive compulsive disorder , tantrums, and impulsive behaviors ( impulse control disorder ). Problems with speech and language are also common. Affected individuals may often have stuttering, difficulty with sound production, or

1320-461: The active site of the enzyme. This orientation of substrate and cofactor allows SAM to dissociate without disrupting substrate binding and can lead to multiple rounds of lysine methylation without substrate dissociation. Although neither a substrate-bound or SAM-bound crystal structure for EZH2 has been determined, STAMP structure alignment with the human SET7/9 methyltransferase shows conserved tyrosine residues in almost identical positions within

1364-587: The nuclear localization signal , the EED and SUZ12 binding sites as well as the conserved SET domain. Most studies have thus far focused on the longer isoform EZH2α, but EZH2β, which lacks exons 4 and 8, has been shown to be active. Furthermore, PRC2/EZH2β complexes act on distinct genes from that of its PRC2/EZH2α counterpart suggesting that each isoform may act to regulate a specific subset of genes. Additional evidence suggests that EZH2 may also be capable of lysine methylation independent of association with PRC2, when EZH2

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1408-515: The pKa of the substrate lysine residue while simultaneously providing a channel for water to access the lysine side chain within the interior of the active site. Bulk solvent water can then easily deprotonate the lysine side chain, activating it for nucleophilic attack of the SAM cofactor in an S N 2 -like reaction resulting in transfer of the methyl group from SAM to the lysine side chain. EZH2 primarily catalyzes mono- and di-methylation of H3K27 but

1452-572: The Japanese population, the most common genetic change leading to Sotos syndrome deletes genetic material from the region of chromosome 5 containing the NSD1 gene. In other populations, small mutations within the NSD1 gene occur more frequently. Genetic changes involving the NSD1 gene prevent one copy of the gene from producing any functional protein. It is unclear how a reduced amount of this protein during development leads to learning disabilities, overgrowth, and

1496-503: The NSD1 gene may also be another cause for confusion. The NSD1 gene provides instructions for making a protein that is involved in normal growth and development. Deletions and mutations in the NSD1 gene is a common cause for patients with Sotos syndrome and in some cases for Weaver syndrome as well. Features distinguishing Weaver syndrome from Sotos syndrome include broad forehead and face, ocular hypertelorism , prominent wide philtrum , micrognathia , deep-set nails, retrognathia with

1540-811: The South West Thames Regional Genetic Service at St George's Hospital in London, based on their detection rate among a cohort of patients within their Childhood Overgrowth Study, estimated a prevalence rate similar to that of Sotos syndrome, around 1 in 15,000. EZH2 4MI0 , 4MI5 , 5HYN , 5IJ8 , 5IJ7 2146 14056 ENSG00000106462 ENSMUSG00000029687 Q15910 Q61188 NM_001203247 NM_001203248 NM_001203249 NM_004456 NM_152998 NM_001146689 NM_007971 NP_001190176 NP_001190177 NP_001190178 NP_004447 NP_694543 NP_001140161 NP_031997 Enhancer of zeste homolog 2 (EZH2)

1584-474: The control of mammalian gene expression and have a functional role in heterochromatin formation, X-chromosome inactivation and transcriptional regulation. In mammalian chromosomes, histone lysine methylation can either activate or repress genes depending the site of methylation. Recent work has shown that at least part of the silencing function of the EZH2 complex is the methylation of histone H3 on lysine 27. Methylation, and other modifications, take place on

1628-620: The following features: Other features may include loose skin, thin deep-set nails, thin hair, short ribs, limited elbow and knee extension, camptodactyly , and a coarse, low-pitched voice. Delayed development of motor skills such as sitting, standing, and walking are commonly exhibited in early childhood. Patients with Weaver syndrome typically have mild intellectual disability with poor coordination and balance. They also have some neurological abnormalities such as speech delay , epilepsy , intellectual disability , hypotonia or hypertonia , and behavioral problems. The cause for Weaver syndrome

1672-753: The histone methyltransferase NSD1 gene on chromosome 5q35 . The functions of NSD1 are not clearly known, but it is thought to act as a factor in influencing transcription, which contains domains involved in chromatin-mediated regulation during development. Most cases are found to be sporadic, with no family history of the syndrome, although there have been a few cases in families where autosomal dominant inheritance has been reported. Weaver syndrome and Sotos syndrome are often mistaken for one another due to their significant phenotypic overlap and similarities. Clinical features shared by both syndromes include overgrowth in early development, advanced bone age, developmental delay, and prominent macrocephaly . Mutations in

1716-569: The histones. Methyl modifications can affect the binding of proteins to these histones and either activate or inhibit transcription . EZH2 is a member of the SET domain family of lysine methyltransferases which function to add methyl groups to lysine side chains of substrate proteins. SET methyltransferases depend on a S-Adenosyl methionine (SAM) cofactor to act as a methyl donor for their catalytic activity. SET domain proteins differ from other SAM-dependent methyltransferases in that they bind their substrate and SAM cofactor on opposite sides of

1760-581: The methylation activity of the enzyme is not mediated by complex formation. In breast cancer cells, EZH2 activates genes that promote cell proliferation and survival. It can also activate regulatory genes like c-myc and cyclin D1 by interacting with Wnt signaling factors. Importantly, the mutation of tyrosine 641 in the active SET domain to a number of different amino acids is a common feature of some B-cell lymphomas. Developing an inhibitor of EZH2 and preventing unwanted histone methylation of tumor suppressor genes

1804-401: The other features of Sotos syndrome. About 95 percent of Sotos syndrome cases occur by spontaneous mutation . Most of these cases result from new mutations involving the NSD1 gene. A few families have been described with more than one affected family member. These inherited cases enabled researchers to determine that Sotos syndrome has an autosomal dominant pattern of inheritance. Diagnosis

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1848-399: The putative active site of EZH2. It had been previously suggested that tyrosine 726 in the EZH2 active site was acting as a general base to de-protonate the substrate lysine but kinetic isotope effects have indicated that active site residues are not directly involved in the chemistry of the methyltransferase reaction. Instead these experiments support a mechanism in which the residues lower

1892-460: The risk of specific types of cancer. If persons with this disorder have any increased cancer risk, their risk is only slightly greater than that of the general population. Mutations in the NSD1 gene cause Sotos syndrome. The NSD1 gene provides instructions for making a protein (histone methyltransferase) that is involved in normal growth and development. The function of this protein is unknown, however. In

1936-677: Was identified in 2011 as autosomal dominant mutations in the EZH2 gene on chromosome 7q36 . EZH2 (Enhancer of Zeste, Drosophila, homolog 2) is the second histone methyltransferase associated with human overgrowth. It encodes the catalytic component of the PRC2 protein complex (Polycomb Repressive Complex 2), which regulates chromatin structure and gene expression, and has been found to repress transcription. EZH2 also has critical roles in stem cell maintenance and cell lineage determination, such as osteogenesis , myogenesis , lymphopoiesis and hematopoiesis . It can also be associated with mutations in

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