Disease relevance of ATRX

• Using this approach, we have shown that in individuals with myelodysplasia associated with alpha-thalassemia (ATMDS), somatic mutations of the gene encoding the chromatin remodeling factor ATRX cause an unexpectedly severe hematological phenotype compared with the wide spectrum of inherited mutations affecting this gene [1].
• Mutations in ATRX give rise to characteristic developmental abnormalities including severe mental retardation, facial dysmorphism, urogenital abnormalities and alpha-thalassaemia [2].
• Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS) [1].
• ATRX syndrome is characterized by X-linked mental retardation associated with alpha-thalassemia [3].
• Acquired somatic mutations in ATRX, an X-linked gene encoding a chromatin-associated protein, were recently identified in 4 patients with the rare subtype of myelodysplastic syndrome (MDS) associated with thalassemia (ATMDS) [4].

Psychiatry related information on ATRX

• Mutations in PHD-like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome [5].
• METHODS.: Swiss residents in the Geneva Gay Men's Health Survey (GGMHS, n=477) were matched with controls from the Swiss Health Survey (SHS, n=477) along sex, age, nationality, and region of residence and compared along standard indicators of health status, health behaviors, and health care utilization [6].
• Evidence-based strategies exist to help pregnant and parenting smokers to quit, to discourage young people from becoming smokers and to reduce exposure of infants to SHS [7].
• At Samaritan Health System (SHS), an integrated health care delivery system based in Phoenix, technology management provides tools to improve decision making and assist in the system's integration strategy as well as control expenses [8].
• We propose that disruption of the MeCP2-ATRX interaction leads to pathological changes that contribute to mental retardation [9].

High impact information on ATRX

• Moreover, at metaphase, some ATRX is localized at or close to the ribosomal DNA (rDNA) arrays on the short arms of human acrocentric chromosomes [2].
• We have recently shown that ATRX is localized to pericentromeric heterochromatin during interphase and mitosis, suggesting that ATRX might exert other chromatin-mediated effects in the nucleus [2].
• Here we show that mutations in ATRX give rise to changes in the pattern of methylation of several highly repeated sequences including the rDNA arrays, a Y-specific satellite and subtelomeric repeats [2].
• Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation [2].
• XNP mutation in a large family with Juberg-Marsidi syndrome [10].

Chemical compound and disease context of ATRX

• In this paper, we report a mutation in XNP, segregating in a family presenting an "ATR-X' phenotype without alpha-thalassemia, that causes a proline to serine transition in the helicase II domain [11].
• To maximize the expression of the cephalosporin-C deacetylase (CAH) gene isolated from Bacillus subtilis SHS 0133 in Escherichia coli, a series of expression plasmids was constructed with various spacings between the Shine-Dalgarno sequence and the ATG initiation codon [12].

Biological context of ATRX

• The unexpected association of a putative transcriptional regulator with highly repetitive DNA provides a potential explanation for the variability in phenotype of patients with identical mutations in the ATRX gene [13].
• Surprisingly, active homologues of ATRX were detected on the marsupial Y as well as the X chromosome [14].
• Using indirect immunofluorescence and confocal microscopy we have shown that ATRX protein is associated with pericentromeric heterochromatin during interphase and mitosis [13].
• To explore further the role of ATRX in mammalian sex differentiation, the homologous gene was cloned and characterized in a marsupial [14].
• Mutations in the ATRX gene on the human X chromosome cause X-linked alpha-thalassemia and mental retardation [14].

Anatomical context of ATRX

• XY patients with deletions or mutations in this gene display varying degrees of sex reversal, implicating ATRX in the development of the human testis [14].
• Two of the new mutations result in changes in amino acids altered in previously described pedigrees with germ line ATRX mutations (ATR-X syndrome), but the hematologic abnormalities were much more severe in the patients with ATMDS than in the corresponding constitutional cases [4].
• Cell cycle-dependent phosphorylation of the ATRX protein correlates with changes in nuclear matrix and chromatin association [15].
• Loss of ATRX protein caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size [16].
• Acquired mutations in ATRX, a chromatin remodeling gene, have recently been found in 12 patients with typical features of ATMDS, though they have not been detected in MDS patients with similar red blood cell findings but little HbH [17].

Associations of ATRX with chemical compounds

• The encoded protein of 387 amino acids has a cysteine-rich region containing a novel-type zinc finger domain that is conserved in DNMT3A and DNMT3B but also in ATRX, a member of the SNF2 protein family [18].
• Inhibition of histone deacetylases (HDACs) with trichostatin A (TSA) disrupted ATRX binding to the centromeres of hyperacetylated chromosomes resulting in abnormal chromosome alignments at metaphase II (MII) [19].
• Meiotic resumption also coincides with deacetylation of histone H4 at lysine 5 (H4K5 Ac) while ATRX and histone H3 methylated on lysine 9 (H3K9) remained bound to the centromeres and interstitial regions of condensing chromosomes, respectively [19].
• Strikingly, overexpression of Rad54p can functionally suppress the UV and methyl methanesulfonate sensitivity caused by a deletion of the RAD51 gene [20].
• Cells deleted for Brca2 exon 27 are hypersensitive to gamma-radiation, streptonigrin, mitomycin C and camptothecin and mildly resistant to ICRF-193 which is similar to HR defective cells null for Rad54 [21].

Physical interactions of ATRX

• By immunoprecipitation from HeLa extract, we found that ATRX is in a complex with transcription cofactor Daxx [3].
• Colocalization was observed with the phosphoserine-15 form of p53 at presumed DNA processing sites after the induction of DNA breaks. hRAD54 bound directly to the p53 COOH terminus in vitro without a nucleic acid intermediate [22].

Other interactions of ATRX

• Taken together, the results suggest that ATRX functions in conjunction with Daxx in a novel chromatin-remodeling complex [3].
• There is no evidence for a Y-borne ATRX homologue in mouse or human, implying that this gene has been lost in eutherians and its role supplanted by the evolution of SRY from SOX3 as the dominant determiner of male differentiation [14].
• The pooled error rates for genomic DNA were: TPRD (A)8, TGFBR2 (A)10, and ATRX (T)13: 1%+/-0.41, 15.8%+/-1.3, and 31.3%+/-2.9, while those for RNA were: 3.8%+/-0.5, 19.3%+/-2.1, and 54.3%+/-1.8, respectively [23].
• These results show that rAAV gene targeting requires the Rad51/Rad54 pathway of HR [24].
• We also define a new class of variant PxVxL CSD-binding motifs in Sp100A, LBR, and ATRX [25].

Analytical, diagnostic and therapeutic context of ATRX

• Using indirect immunofluorescence and biochemical fractionation, we demonstrate that the ATRX protein has a punctate nuclear staining pattern and that it is tightly associated with the nuclear matrix at interphase [15].
• Here we describe a series of novel point mutations in ATRX detected in archival DNA samples from marrow and/or blood of patients with ATMDS by use of denaturing high-performance liquid chromatography (DHPLC), a technique sensitive to low-level mosaicism [4].
• In situ hybridization studies in mouse reveal precocious, widespread expression of the murine homologue of XH2 at early stages of embryogenesis, and more restricted expression during late developmental stages and at birth [26].
• Thus, gene expression profiling identified AML patients with divergent prognoses within the FLT3-MU group, and the RUNX3 to ATRX expression ratio should be a useful prognostic indicator in these patients [27].
• Similarly, while selective ablation of ATRX by antibody microinjection and RNA interference (RNAi) had no effect on the progression of meiosis, it had severe consequences for the alignment of chromosomes on the metaphase II spindle [19].

References