Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability

Tatton‐Brown, Katrina; Seal, Sheila; Ruark, Elise; Harmer, Jenny E.; Ramsay, Emma; Duarte, Silvana Del Vecchio; Zachariou, Anna; Hanks, Sandra; O’Brien, Eleanor M.; Aksglæde, Lise; Baralle, Diana; Dabir, Tabib; Gener, Blanca; Goudie, David; Homfray, Tessa; Kumar, Ajith; Pilz, Daniela T.; Selicorni, Angelo; Temple, I. Karen; Maldergem, Lionel Van; Yachelevich, Naomi; Montfort, Robert van; Rahman, Nazneen

doi:10.1038/ng.2917

Cited by 309 publications

(293 citation statements)

References 27 publications

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“…Given that the size of inter/intragenic regions far exceeds that of H3K4me3/CGI, we suggest that wild-type and R mutant bind to the unmodified H3 N-terminus with higher affinity and so have less opportunity to relocate. Alterations in this balance, leading to even modest changes in de novo DNA methylation, may contribute to human pathologies, as mutations in ADD 3a are found in numerous diseases such as acute myeloid leukemia (Yan et al, 2011) and overgrowth syndrome associated with intellectual disability (Tatton-Brown et al, 2014). To our knowledge, the exact mutations engineered in our study have not yet been associated with disease.…”

Section: Discussionmentioning

confidence: 80%

Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs

Noh¹,

Wang²,

Kim³

et al. 2018

Molecular Cell

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Section: Discussionmentioning

confidence: 80%

Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs

Noh¹,

Wang²,

Kim³

et al. 2018

Molecular Cell

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“…Therefore, a deficiency of one epigenetic modification may lead to secondary abnormalities of another epigenetic modification. Deficiency of the other de novo methyltransferase (DNMT3A) also suggests interplay among DNA methylation, histone modifications, and imprinting, as the phenotype observed with haploinsufficiency of DNMT3A (a component of the DNA methylation machinery) involves overgrowth (Tatton-Brown et al 2014), a phenotype also shared among patients with defects of imprinting and with defects of components of the histone machinery (Fig. 1).…”

Section: Do Downstream Epigenetic Consequences Explain the Entire Phementioning

confidence: 99%

The Mendelian disorders of the epigenetic machinery

2015

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The Mendelian disorders of the epigenetic machinery are genetic disorders that involve disruption of the various components of the epigenetic machinery (writers, erasers, readers, and remodelers) and are thus expected to have widespread downstream epigenetic consequences. Studying this group may offer a unique opportunity to learn about the role of epigenetics in health and disease. Among these patients, neurological dysfunction and, in particular, intellectual disability appears to be a common phenotype; however, this is often seen in association with other more specific features in respective disorders. The specificity of some of the clinical features raises the question whether specific cell types are particularly sensitive to the loss of these factors. Most of these disorders demonstrate dosage sensitivity as loss of a single allele appears to be sufficient to cause the observed phenotypes. Although the pathogenic sequence is unknown for most of these disorders, there are several examples where disrupted expression of downstream target genes accounts for a substantial portion of the phenotype; hence, it may be useful to systematically map such disease-relevant target genes. Finally, two of these disorders (Rubinstein-Taybi and Kabuki syndromes) have shown post-natal rescue of markers of the neurological dysfunction with drugs that lead to histone deacetylase inhibition, indicating that some of these disorders may be treatable causes of intellectual disability.

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“…The long isoform also contains 219 extra amino acids at the amino terminus, which have been shown to enhance the DNA-binding affinity and methylation activity of the protein in vitro (Suetake et al 2011). De novo germline mutations in each of the three major domains occur in the recently described Tatton-BrownRahman syndrome (or DNMT3A overgrowth syndrome), which is characterized by tall stature, a distinctive facial appearance, and intellectual disability (Tatton-Brown et al 2014).…”

Section: Dnmt3a Structurementioning

confidence: 99%

DNMT3A in Leukemia

Brunetti

Gundry

Goodell

2016

Cold Spring Harb Perspect Med

156

108

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DNA methylation is an epigenetic process involved in development, aging, and cancer. Although the advent of new molecular techniques has enhanced our knowledge of how DNA methylation alters chromatin and subsequently affects gene expression, a direct link between epigenetic marks and tumorigenesis has not been established. DNMT3A is a de novo DNA methyltransferase that has recently gained relevance because of its frequent mutation in a large variety of immature and mature hematologic neoplasms. DNMT3A mutations are early events during cancer development and seem to confer poor prognosis to acute myeloid leukemia (AML) patients making this gene an attractive target for new therapies. Here, we discuss the biology of DNMT3A and its role in controlling hematopoietic stem cell fate decisions. In addition, we review how mutant DNMT3A may contribute to leukemogenesis and the clinical relevance of DNMT3A mutations in hematologic cancers. DNA methylation is an epigenetic modification involved in key cellular processes such as transcriptional repression, genomic imprinting, and the suppression of repetitive elements. The first suggestion of a link between DNA methylation and cancer was the observation that human cancers tend to display global hypomethylation compared with normal controls (Feinberg and Vogelstein 1983). Subsequently, the field switched attention to focally hypermethylated regions with the hypothesis that epigenetic silencing of tumor suppressor genes through promoter hypermethylation would drive gene silencing, obviating the need for genetic inactivation of these pathways (Jones and Laird 1999). Investigators then began looking for possible genes/pathways responsible for the observed methylation changes.The deposition and maintenance of DNA methyl marks is orchestrated by DNA methyltransferases. In mammals, three genes encoding proteins with DNA methyltransferase activity have been identified: DNMT1, DNMT3A, and DNMT3B (Okano et al. 1998). DNMT3A and DNMT3B proteins are responsible for establishing the patterns of DNA methylation early in embryogenesis through de novo methylation of unmethylated CpG sites , and DNMT1 maintains such patterns throughout cell division by targeting hemimethylated 6 These authors contributed equally to this work.

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Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability

Cited by 309 publications

References 27 publications

Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs

Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs

The Mendelian disorders of the epigenetic machinery

DNMT3A in Leukemia

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