Alpha-thalassemia mental retardation syndrome (ATRX), also called alpha-thalassemia X-linked intellectual disability syndrome, nondeletion type or ATR-X syndrome , is an X-linked recessive condition associated with a mutation in the ATRX gene. Males with this condition tend to be moderately intellectually disabled and have physical characteristics including coarse facial features , microcephaly (small head size), hypertelorism (widely spaced eyes), a depressed nasal bridge, a tented upper lip and an everted lower lip. Mild or moderate anemia , associated with alpha-thalassemia , is part of the condition. Females with this mutated gene have no specific signs or features, but if they do, they may demonstrate skewed X chromosome inactivation .
34-463: "The role of ATRX as a regulator of heterochromatin dynamics raises the possibility that mutations in ATRX may lead to downstream transcriptional effects across the complex of genes or repetitive regions involved in the global context of the disorder, in addition to explaining phenotypical differences in these patients. For example, ATRX mutations affect the expression of alpha-globin gene cluster , causing alpha-thalassemia." ATRX interacts with
68-471: A barrier in rare cases where constitutive heterochromatin and highly active genes are juxtaposed (e.g. the 5'HS4 insulator upstream of the chicken β-globin locus, and loci in two Saccharomyces spp. ). All cells of a given species package the same regions of DNA in constitutive heterochromatin , and thus in all cells, any genes contained within the constitutive heterochromatin will be poorly expressed . For example, all human chromosomes 1 , 9 , 16 , and
102-474: A histone H3 lysine-4 trimethyltransferase, which is a known target for ATRX , and 2-BHMT2 encodes for betaine-homocysteine methyltransferase, which catalyzes the methylation of homocysteine . ATR association can be separated into two groups. ATR-16 syndrome patients have a 1-2Mb deletion on the top of the chromosome 16 p-arm and are associated with a Mendelian inheritance of a-thalassemia. ATR-X syndrome patients have no deletion in chromosome 16, a-thalassemia
136-422: A number of models, two epigenetic models are popular. One is the cis -spreading of the heterochromatin past the rearrangement breakpoint. The trans -interactions come in when the cis- spreading model is unable to explain certain phenomena. According to this model, the heterochromatin forces an altered chromatin conformation on the euchromatic region. Due to this, the transcriptional machinery cannot access
170-461: A role in the DNA damage response, DNA repair and in the fidelity of replication . Saccharomyces cerevisiae , or budding yeast, is a model eukaryote and its heterochromatin has been defined thoroughly. Although most of its genome can be characterized as euchromatin, S. cerevisiae has regions of DNA that are transcribed very poorly. These loci are the so-called silent mating type loci (HML and HMR),
204-471: Is a tightly packed form of DNA or condensed DNA , which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive heterochromatin and facultative heterochromatin . Both play a role in the expression of genes . Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed; however, according to Volpe et al. (2002), and many other papers since, much of this DNA
238-553: Is in fact transcribed, but it is continuously turned over via RNA-induced transcriptional silencing (RITS). Recent studies with electron microscopy and OsO 4 staining reveal that the dense packing is not due to the chromatin. Constitutive heterochromatin can affect the genes near itself (e.g. position-effect variegation ). It is usually repetitive and forms structural functions such as centromeres or telomeres , in addition to acting as an attractor for other gene-expression or repression signals. Facultative heterochromatin
272-452: Is inserted onto the X chromosome, variable silencing of the allele is seen. Variegation is, however, observed only in the female having this insertion along with a homozygous mutation in the original coat color gene. The wild-type allele gets inactivated due to heterochromatinization. In plants, PEV has been observed in Oenothera blandina . The silencing of euchromatic genes occurs when
306-450: Is passed to a male, they will have a higher percent of heterochromatin. The ATR-X locus spans the control center Xist , which regulates X-inactivation. When there is a XH2 mutation in the ATR-X locus, this indicates Xist to inactivate the chromosome increasing the amount of heterochromatin in males. Epigenetics is also present among transcriptional regulators. ATR-X is caused by XH2 mutations in
340-414: Is rare, and this syndrome is consistent with X-linked recessive inheritance. However, both groups have similar phenotypes. The phenotypes resulting from ATR-X are due to skewed x-inactivation. When X-inactivation occurs randomly, half of the cells in the carrier female would contain the abnormality. When X-inactivation is skewed, more than 50% of one X chromosome are becoming inactive, and if that X-chromosome
374-488: Is the Barr body of the second, inactivated X-chromosome in a female. Heterochromatin has been associated with several functions, from gene regulation to the protection of chromosome integrity; some of these roles can be attributed to the dense packing of DNA, which makes it less accessible to protein factors that usually bind DNA or its associated factors. For example, naked double-stranded DNA ends would usually be interpreted by
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#1732858626659408-492: Is the Drosophila w (speak white-mottled-4) translocation . In this mutation , an inversion on the X chromosome placed the white gene next to pericentric heterochromatin, or a sequence of repeats that becomes heterochromatic. Normally, the white gene is expressed in every cell of the adult Drosophila eye resulting in a red-eye phenotype . In the w[m4] mutant, the eye color was variegated (red-white mosaic colored) where
442-419: Is the result of genes that are silenced through a mechanism such as histone deacetylation or Piwi-interacting RNA (piRNA) through RNAi . It is not repetitive and shares the compact structure of constitutive heterochromatin. However, under specific developmental or environmental signaling cues, it can lose its condensed structure and become transcriptionally active. Heterochromatin has been associated with
476-539: The Y-chromosome contain large regions of constitutive heterochromatin. In most organisms, constitutive heterochromatin occurs around the chromosome centromere and near telomeres. The regions of DNA packaged in facultative heterochromatin will not be consistent between the cell types within a species, and thus a sequence in one cell that is packaged in facultative heterochromatin (and the genes within are poorly expressed) may be packaged in euchromatin in another cell (and
510-451: The di- and tri -methylation of H3K9 in certain portions of the human genome. H3K9me3 -related methyltransferases appear to have a pivotal role in modifying heterochromatin during lineage commitment at the onset of organogenesis and in maintaining lineage fidelity. Chromatin is found in two varieties: euchromatin and heterochromatin. Originally, the two forms were distinguished cytologically by how intensely they get stained –
544-447: The white gene was expressed in some cells in the eyes and not in others. The mutation was described first by Hermann Muller in 1930. PEV is a heterochromatin-induced gene inactivation . Gene silencing phenomena similar to this have also been observed in S. cerevisiae and S. pombe . Typically, the barrier DNA sequences prevent the heterochromatic region from spreading into the euchromatin but they are no longer present in
578-819: The RITS complex and the RNA-directed RNA polymerase complex (RDRC), are part of an RNAi machinery involved in the initiation, propagation and maintenance of heterochromatin assembly. These two complexes localize in a siRNA -dependent manner on chromosomes, at the site of heterochromatin assembly. RNA polymerase II synthesizes a transcript that serves as a platform to recruit RITS, RDRC and possibly other complexes required for heterochromatin assembly. Both RNAi and an exosome-dependent RNA degradation process contribute to heterochromatic gene silencing. These mechanisms of Schizosaccharomyces pombe may occur in other eukaryotes. A large RNA structure called RevCen has also been implicated in
612-407: The austerity of the variegated phenotype can be altered by the distance of the heterochromatic region from the breakpoint. This suggests that trans -interactions are crucial for PEV. These are interactions between the different heterochromatic regions and the global chromosomal organisation in the interphase nucleus. The rearrangements due to PEV places the reporter gene in a new compartment of
646-424: The cell as damaged or viral DNA, triggering cell cycle arrest, DNA repair or destruction of the fragment, such as by endonucleases in bacteria. Some regions of chromatin are very densely packed with fibers that display a condition comparable to that of the chromosome at mitosis . Heterochromatin is generally clonally inherited; when a cell divides, the two daughter cells typically contain heterochromatin within
680-914: The euchromatin is less intense, while heterochromatin stains intensely, indicating tighter packing. Heterochromatin was given its name for this reason by botanist Emil Heitz who discovered that heterochromatin remained darkly stained throughout the entire cell cycle, unlike euchromatin whose stain disappeared during interphase. Heterochromatin is usually localized to the periphery of the nucleus . Despite this early dichotomy, recent evidence in both animals and plants has suggested that there are more than two distinct heterochromatin states, and it may in fact exist in four or five 'states', each marked by different combinations of epigenetic marks. Heterochromatin mainly consists of genetically inactive satellite sequences , and many genes are repressed to various extents, although some cannot be expressed in euchromatin at all. Both centromeres and telomeres are heterochromatic, as
714-435: The flies that inherit certain chromosomal rearrangements. PEV is a position effect because the change in position of a gene from its original position to somewhere near a heterochromatic region has an effect on its expression . The effect is the variegation in a particular phenotype i.e., the appearance of irregular patches of different colour(s), due to the expression of the original wild-type gene in some cells of
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#1732858626659748-399: The gene which leads to the inhibition of transcription. In other words, the heterochromatin spreads and causes gene silencing by packaging the normally euchromatic region. But this model fails to explain some aspects of PEV. For example, variegation can be induced in a gene located several megabases from the heterochromatin-euchromatin breakpoint due to rearrangements in that breakpoint. Also,
782-423: The genes within are no longer silenced). However, the formation of facultative heterochromatin is regulated, and is often associated with morphogenesis or differentiation . An example of facultative heterochromatin is X chromosome inactivation in female mammals: one X chromosome is packaged as facultative heterochromatin and silenced, while the other X chromosome is packaged as euchromatin and expressed. Among
816-535: The molecular components that appear to regulate the spreading of heterochromatin are the Polycomb-group proteins and non-coding genes such as Xist . The mechanism for such spreading is still a matter of controversy. The polycomb repressive complexes PRC1 and PRC2 regulate chromatin compaction and gene expression and have a fundamental role in developmental processes. PRC-mediated epigenetic aberrations are linked to genome instability and malignancy and play
850-481: The nucleus where the transcriptional machinery required is not available, thus silencing the gene and modifying the chromatin structure. These two mechanisms affect each other as well. Which mechanism dominates to influence the phenotype depends upon the type of heterochromatin and the intricacy of the rearrangement. The mutations in mus genes are the candidates as PEV modifiers, as these genes are involved in chromosome maintenance and repair. Chromosome structure in
884-465: The patient has ATR-X syndrome. However, it is common within ATR-X patients to have global hypermethylation of usually unmethylated regions, like CpG islands and promoters . Several of the genes that undergo methylation changes are responsible for biosynthetic , metabolic, and methylation processes, and 42.5% of these genes are present in the telomeric and pericentromeric regions. A couple of these genes include: PRDM9 and 2- BHMT2 . PRDM9 encodes for
918-417: The production of siRNAs to mediate heterochromatin formation in some fission yeast. Position-effect variegation Position-effect variegation ( PEV ) is a variegation caused by the silencing of a gene in some cells through its abnormal juxtaposition with heterochromatin via rearrangement or transposition . It is also associated with changes in chromatin conformation . The classical example
952-475: The rDNA (encoding ribosomal RNA), and the sub-telomeric regions. Fission yeast ( Schizosaccharomyces pombe ) uses another mechanism for heterochromatin formation at its centromeres. Gene silencing at this location depends on components of the RNAi pathway. Double-stranded RNA is believed to result in silencing of the region through a series of steps. In the fission yeast Schizosaccharomyces pombe , two RNAi complexes,
986-511: The region Xq13.3, and XH2 belongs to the subgroup SNF2. This group is important for regulating the transcription of the alpha genes. If ATR-X is suspected based on symptoms, diagnosis can be done via Genome testing. If the results are conclusive with ATR-X syndrome, female members of the same family will often be asked to partake in genome testing to see if anyone else in the family may possess this gene. Heterochromatin Heterochromatin
1020-434: The same regions of DNA, resulting in epigenetic inheritance . Variations cause heterochromatin to encroach on adjacent genes or recede from genes at the extremes of domains. Transcribable material may be repressed by being positioned (in cis ) at these boundary domains. This gives rise to expression levels that vary from cell to cell, which may be demonstrated by position-effect variegation . Insulator sequences may act as
1054-463: The tissue but not in others, as seen in the eye of mutated Drosophila melanogaster . However, it is possible that the effect of the silenced gene is not phenotypically visible in some cases. PEV was observed first in Drosophila because it was one of the first organisms on which X-ray irradiation was used as a mutation inducer. X-rays can cause chromosomal rearrangements that can result in PEV. Among
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1088-480: The transcription co-factor DAXX and the alpha-globin gene cluster. Together they are all responsible for depositing the histone H3.3 at telomeric and pericentromeric regions. They are also responsible for regulating gene expression at these regions. ATRX is characterized by hypo- and hypermethylated regions. It's important to recognize that having a mutation in the ATRX gene does not necessarily guarantee that
1122-434: The vicinity of the breakpoint appears to be an important determinant of the gene inactivation process. Six second chromosomal mus mutations were isolated with w . A copy of wild-type white gene was placed adjacent to heterochromatin. The different mus mutants that were taken were: mus 201 , mus 205 , mus 208 , mus 209 , mus 210 , mus 211 . A stock was constructed with the replacement of standard X-chromosome with w . It
1156-400: Was observed that the suppression of PEV is not a characteristic of mus mutations in general. Only for homozygous mus 209 , the variegation was significantly suppressed. Also, when homozygous, 2735 and D-1368 and all heteroallelic combinations of its Pcna mutations strongly suppress PEV. In mouse, variegating coat colour has been observed. When an autosomal region carrying a fur color gene
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