Mutations in the chromatin-associated protein ATRX

Gibbons, Richard J.; Wada, Takahito; Fisher, Christopher A.; Malik, N; Mitson, Matthew; Steensma, David P.; Fryer, Alan; Goudie, David; Krantz, Ian D.; Traeger-Synodinos, Joanne

doi:10.1002/humu.20734

Cited by 160 publications

(173 citation statements)

References 33 publications

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“…Thus, ATRX protein is essential for normal development and cortical organization of the brain. Since null ATRX mutations do not exist in humans, mutation creating premature stop codon results in low-level expression of full-length ATRX protein in humans (Gibbons et al, 2008). Analysis of the 5Ј end of the ATRX gene reveals that a truncated ATRX protein is transcribed from a downstream AUG start codon at residue 40 in exon 2 (Howard et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in theATRXMutant Mouse Brain

Shioda¹,

Beppu²,

Fukuda³

et al. 2011

J. Neurosci.

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In humans, mutations in the gene encoding ATRX, a chromatin remodeling protein of the sucrose-nonfermenting 2 family, cause several mental retardation disorders, including ␣-thalassemia X-linked mental retardation syndrome. We generated ATRX mutant mice lacking exon 2 (ATRX ⌬E2 mice), a mutation that mimics exon 2 mutations seen in human patients and associated with milder forms of retardation. ATRX ⌬E2 mice exhibited abnormal dendritic spine formation in the medial prefrontal cortex (mPFC). Consistent with other mouse models of mental retardation, ATRX ⌬E2 mice exhibited longer and thinner dendritic spines compared with wild-type mice without changes in spine number. Interestingly, aberrant increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity was observed in the mPFC of ATRX ⌬E2 mice. Increased CaMKII autophosphorylation and activity were associated with increased phosphorylation of the Rac1-guanine nucleotide exchange factors (GEFs) T-cell lymphoma invasion and metastasis 1 (Tiam1) and kalirin-7, known substrates of CaMKII. We confirmed increased phosphorylation of p21-activated kinases (PAKs) in mPFC extracts. Furthermore, reduced protein expression and activity of protein phosphatase 1 (PP1) was evident in the mPFC of ATRX ⌬E2 mice. In cultured cortical neurons, PP1 inhibition by okadaic acid increased CaMKII-dependent Tiam1 and kalirin-7 phosphorylation. Together, our data strongly suggest that aberrant CaMKII activation likely mediates abnormal spine formation in the mPFC. Such morphological changes plus elevated Rac1-GEF/PAK signaling seen in ATRX ⌬E2 mice may contribute to mental retardation syndromes seen in human patients.

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Section: Discussionmentioning

confidence: 99%

Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in theATRXMutant Mouse Brain

Shioda¹,

Beppu²,

Fukuda³

et al. 2011

J. Neurosci.

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“…In addition to ATR-X syndrome, mutations in the ATRX gene have now been found in many other forms of syndromal X-linked MR (reviewed in Gibbons et al 2008) and it is also the disease gene associated with the occurrence of athalassemia in myelodysplasia (see later section).…”

Section: Mutations Of the Atrx Gene And Their Associated Phenotypementioning

confidence: 99%

“…To date, 113 different constitutional mutations have been documented in 182 independent families with ATR-X syndrome (reviewed in Gibbons et al 2008). Missense mutations are clustered in two regions: the ADD domain, and the helicase domain.…”

Section: Mutations Of the Atrx Gene And Their Associated Phenotypementioning

confidence: 99%

-Thalassemia, Mental Retardation, and Myelodysplastic Syndrome

Gibbons

2012

Cold Spring Harbor Perspectives in Medicine

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“…As further evidence of the interplay between different epigenetic modifications, ATRX mutations are also associated with abnormal patterns of DNA methylation. 91 …”

Section: Chromatin Remodelingmentioning

confidence: 99%

Epigenetic Dysregulation in Cancer

Muntean

Hess

2009

The American Journal of Pathology

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One of the great paradoxes in cellular differentiation is how cells with identical DNA sequences differentiate into so many different cell types. The mechanisms underlying this process involve epigenetic regulation mediated by alterations in DNA methylation, histone posttranslational modifications, and nucleosome remodeling. It is becoming increasingly clear that disruption of the "epigenome" as a result of alterations in epigenetic regulators is a fundamental mechanism in cancer. This has major implications for the future of both molecular diagnostics as well as cancer chemotherapy. Epigenetics is a rapidly evolving field focused on explaining how heritable changes in gene expression occur that do not involve changes in nucleotide sequence.1 Epigenetic regulation of transcription can be mediated through DNA methylation, histone modifications including histone acetylation, phosphorylation, methylation, ubiquitination, and proteolysis, and alterations in chromatin remodeling. Importantly, increasing evidence shows that epigenetic deregulation is a common mechanism in cancer. The role of DNA methylation in cancer has been extensively studied, and a number of excellent reviews have been published on this topic.2-4 More recently, it has become clear that histone modifications, as well as disruption of chromatin remodeling machinery, play a fundamental role in cancer, and this is our primary focus in this review. It is important to recognize that these three types of epigenetic regulation are highly interdependent. For example, patterns of histone methylation are important for establishing patterns of DNA methylation. Chromatin remodeling, in turn, is programmed in part by changes in DNA methylation and histone modifications. 3 DNA MethylationCpG-rich sequences are generally rare in the mammalian genome except for in so-called CpG islands, which are associated with centromeres, microsatellite sequences, and the proximal promoter regions of approximately half of all genes. CpG-containing sequences are cytosine methylated by a family of DNA methyltransferases or DNMTs (to date, unequivocal evidence for DNA demethylases is lacking). These methyltransferases generally exempt promoter-associated CpG islands, where Ͻ20% are CpG methylated.

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Mutations in the chromatin-associated protein ATRX

Cited by 160 publications

References 33 publications

Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in theATRXMutant Mouse Brain

Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in theATRXMutant Mouse Brain

-Thalassemia, Mental Retardation, and Myelodysplastic Syndrome

Epigenetic Dysregulation in Cancer

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