Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.37 (DNA methyltransferase)
4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Facioscapulohumeral muscular dystrophy (FSHD) has an unusual molecular etiology. In a putatively heterochromatic subtelomeric region of each chromosome 4 homologue (4q35), unaffected individuals have 11 to about 95 tandem copies of a complex 3.3-kb repeat (D4Z4). Most FSHD patients have less than 10 copies at one allelic 4q35. This has been proposed to lead to the loss of heterochromatinization and, thereby, inappropriate gene expression by position effects, explaining the dominant nature of FSHD and the role of a decreased number of copies of D4Z4 at 4q35 but not at 10q26. Consistent with the proposed heterochromatinization of this repeat, by Southern blot analysis, we found that SmaI, MluI, SacII, and EagI sites in D4Z4 are highly methylated in normal and FSHD cell lines and somatic tissues, including skeletal muscle. Like repeated DNA sequences in the juxtacentromeric heterochromatin of chromosomes 1, 9, and 16, D4Z4 was hypomethylated at numerous CpGs in sperm and in cell lines from patients with an unrelated DNA methyltransferase deficiency syndrome (ICF; immunodeficiency, centromeric region instability, facial anomalies) in contrast to its hypermethylation in non-ICF postnatal somatic tissues. Our data on FSHD samples suggest that the disease-associated 4q35 D4Z4 repeats, which constitute a small percentage of the total D4Z4 repeats, are not generally hypomethylated relative to the other repeats of this sequence. However, in individuals not affected with FSHD, the hypermethylation of tandem, high-copy-number D4Z4 repeats might help stabilize heterochromatinization at allelic 4q35 regions just as hypermethylation elsewhere in the genome has been linked to chromatin compaction.
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PMID:Methylation of the FSHD syndrome-linked subtelomeric repeat in normal and FSHD cell cultures and tissues. 1170 61

ICF (immunodeficiency, centromeric region instability and facial anomalies) is a recessive disease caused by mutations in the DNA methyltransferase 3B gene (DNMT3B). Patients have immunodeficiency, chromosome 1 (Chr1) and Chr16 pericentromeric anomalies in mitogen-stimulated lymphocytes, a small decrease in overall genomic 5-methylcytosine levels and much hypomethylation of Chr1 and Chr16 juxtacentromeric heterochromatin. Microarray expression analysis was done on B-cell lymphoblastoid cell lines (LCLs) from ICF patients with diverse DNMT3B mutations and on control LCLs using oligonucleotide arrays for approximately 5600 different genes, 510 of which showed a lymphoid lineage-restricted expression pattern among several different lineages tested. A set of 32 genes had consistent and significant ICF-specific changes in RNA levels. Half of these genes play a role in immune function. ICF-specific increases in immunoglobulin (Ig) heavy constant mu and delta RNA and cell surface IgM and IgD and decreases in Ig(gamma) and Ig(alpha) RNA and surface IgG and IgA indicate inhibition of the later steps of lymphocyte maturation. ICF-specific increases were seen in RNA for RGS1, a B-cell specific inhibitor of G-protein signaling implicated in negative regulation of B-cell migration, and in RNA for the pro-apoptotic protein kinase C eta gene. ICF-associated decreases were observed in RNAs encoding proteins involved in activation, migration or survival of lymphoid cells, namely, transcription factor negative regulator ID3, the enhancer-binding MEF2C, the iron regulatory transferrin receptor, integrin beta7, the stress protein heme oxygenase and the lymphocyte-specific tumor necrosis factor receptor family members 7 and 17. No differences in promoter methylation were seen between ICF and normal LCLs for three ICF upregulated genes and one downregulated gene by a quantitative methylation assay [combined bisulfite restriction analysis (COBRA)]. Our data suggest that DNMT3B mutations in the ICF syndrome cause lymphogenesis-associated gene dysregulation by indirect effects on gene expression that interfere with normal lymphocyte signaling, maturation and migration.
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PMID:DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes. 1174 35

Inadequate attention has been paid to the frequent and often extensive cancer-associated DNA hypomethylation. This hypomethylation usually includes undermethylation of certain DNA repeats in constitutive heterochromatin, although it is not limited to such sequences. Many cancers display an overall deficiency in the levels of genomic 5-methylcytosine compared to a variety of normal postnatal somatic tissues. The immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome, a rare recessive DNA methyltransferase deficiency disease, results in a small decrease in the extent of global genomic methylation. In ICF, DNA hypomethylation is targeted to the satellite DNA in juxtacentromeric (centromere-adjacent) heterochromatin of chromosomes 1 and 16 (1qh and 16qh), which are prone to rearrangements in ICF lymphoid cells. Also, 1qh and 16qh DNA sequences frequently are hypomethylated in human cancers and rearrangements in their vicinity are overrepresented in cancers. These often lead to chromosome arm imbalances and gene dosage imbalances that could participate in carcinogenesis. Studies of ICF cells suggest that hypomethylation in the normally highly methylated 1qh and 16qh regions predisposes to heterochromatin decondensation in these regions, which in turn leads to elevated levels of rearrangements. Studies of ICF cells also suggest that some of these rearrangements, namely multiradial chromosomes with multiple arms joined in the pericentromeric region, may be unstable intermediates in formation of more stable pericentromeric rearrangements in cancer. Microarray gene expression analysis on ICF and normal lymphoblastoid cell lines suggests that this hypomethylation also may affect gene expression elsewhere in the genome.
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PMID:DNA hypomethylation, cancer, the immunodeficiency, centromeric region instability, facial anomalies syndrome and chromosomal rearrangements. 1216 5

DNA methylation regulates important biological processes and is involved in tumorigenesis and several human diseases, such as Rett and immunodeficiency, centromeric instability and facial anomalies (ICF). The major objective of our research is to investigate the roles of DNA methylation in mammals through genetic analysis of DNA methyltransferase genes in mouse and human. Previously, we found that Dnmt1 knockout embryonic stem (ES) cells are capable of methylating retroviral DNA de novo. In search of enzymes responsible for de novo methylation, we have cloned a novel family of mammalian DNA methyltransferase genes, Dnmt3a and Dnmt3b. Although extensive sequence similarity was found between Dnmt3a and Dnmt3b, little homology was observed between Dnmt1 and Dnmt3a/3b in the catalytic domain as well as in the N-terminal domain. Additionally, biochemical analysis revealed that, unlike Dnmt1, neither Dnmt3a nor Dnmt3b had a strong preference to hemimethylated DNA substrates. Genetic analysis demonstrated that Dnmt3a and Dnmt3b were required for de novo methylation activities in ES cells and during early embryogenesis and were essential for early development. Interestingly, phenotype analyses of single homozygous mice for either Dnmt3a or Dnmt3b suggested that the functions of Dnmt3a and Dnmt3b also were required at the late developmental stage and even at the adult stage.
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PMID:Genetic analyses of DNA methyltransferase genes in mouse model system. 1216 12

ICF syndrome is a rare autosomal recessive disorder characterized by immunodeficiency, centromeric instability, and facial anomalies. It is caused by mutations in a de novo DNA methyltransferase gene, DNMT3B. We here report the first three Japanese cases of ICF syndrome from two unrelated families. All patients had typical facial dysmorphism and immunoglobulin A (IgA) deficiency, but none of them had apparent mental retardation. Cytogenetic analysis of peripheral blood lymphocytes showed chromosomal abnormalities, including multiradial configurations and a stretching of the pericentromeric heterochromatin of chromosomes 1 and 16. Hypomethylation of classical satellite 2 DNA was also observed. Mutation analyses of DNMT3B revealed three novel mutations: patient 1 from the first family was a compound heterozygote for a nonsense mutation (Q42Term) and a missense mutation (R832Q); patients 2 and 3 from the second family were both homozygous for a missense mutation (S282P). The R832Q mutation occurred within the conserved methyltransferase domain, and thus may affect the enzyme activity directly. The S282P mutation, on the other hand, occurred close to the PWWP domain, which is presumably involved in protein-protein interaction. This is the first missense mutation mapped to the N-terminal half of the protein, suggesting that the region plays an important role in the regulation of the DNMT3B enzyme.
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PMID:Three novel DNMT3B mutations in Japanese patients with ICF syndrome. 1223 17

Untreated cultures from normal chorionic villus (CV) or amniotic fluid-derived (AF) samples displayed dramatic cell passage-dependent increases in aberrations in the juxtacentromeric heterochromatin of chromosomes 1 or 16 (1qh or 16qh). They showed negligible levels of chromosomal aberrations in primary culture and no other consistent chromosomal abnormality at any passage. By passage 8 or 9, 82 +/- 7% of the CV metaphases from all eight studied samples exhibited 1qh or 16qh decondensation and 25 +/- 16% had rearrangements in these regions. All six analyzed late-passage AF cultures displayed this regional decondensation and recombination in 54 +/- 16 and 3 +/- 3% of the metaphases, respectively. Late-passage skin fibroblasts did not show these aberrations. The chromosomal anomalies resembled those diagnostic for the ICF syndrome (immunodeficiency, centromeric region instability, and facial anomalies). ICF patients have constitutive hypomethylation at satellite 2 DNA (Sat2) in 1qh and 16qh, generally as the result of mutations in the DNA methyltransferase gene DNMT3B. At early and late passages, CV DNA was hypomethylated and AF DNA was hypermethylated both globally and at Sat2. DNMT1, DNMT3A, or DNMT3B RNA levels did not differ significantly between CV and AF cultures or late and early passages. The high degree of methylation of Sat2 in late-passage AF cells indicates that hypomethylation of this repeat is not necessary for 1qh decondensation. Sat2 hypomethylation may nonetheless favor 1qh and 16qh anomalies because CV cultures, with their Sat2 hypomethylation, displayed 1qh and 16qh decondensation and rearrangements at significantly lower passage numbers than did AF cultures. Also, CV cultures had much higher ratios of ICF-like rearrangements to heterochromatin decondensation in chromosomes 1 and 16. These cultures may serve as models to help elucidate the biological consequences of cancer-associated satellite DNA hypomethylation.
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PMID:Prolonged culture of normal chorionic villus cells yields ICF syndrome-like chromatin decondensation and rearrangements. 1258 36

Immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disease. Mutations in the DNA methyltransferase 3B (DNMT3B) gene are responsible for most ICF cases reported. We investigated the B-cell defects associated with agammaglobulinemia in this syndrome by analyzing primary B cells from 4 ICF patients. ICF peripheral blood (PB) contains only naive B cells; memory and gut plasma cells are absent. Naive ICF B cells bear potentially autoreactive long heavy chain variable regions complementarity determining region 3's (V(H)CDR3's) enriched with positively charged residues, in contrast to normal PB transitional and mature B cells, indicating that negative selection is impaired in patients. Like anergic B cells in transgenic models, newly generated and immature B cells accumulate in PB. Moreover, these cells secrete immunoglobulins and exhibit increased apoptosis following in vitro activation. However, they are able to up-regulate CD86, indicating that mechanisms other than anergy participate in silencing of ICF B cells. One patient without DNMT3B mutations shows differences in immunoglobulin E (IgE) switch induction, suggesting that immunodeficiency could vary with the genetic origin of the syndrome. In this study, we determined that negative selection breakdown and peripheral B-cell maturation blockage contribute to agammaglobulinemia in the ICF syndrome.
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PMID:Defective B-cell-negative selection and terminal differentiation in the ICF syndrome. 1464 8

Despite the wide range of probes commercially available for interphase fluorescence in situ hybridisation (FISH), the supply of locus-specific probes is limited to genes or chromosomal regions commonly altered in genetic diseases or during carcinogenesis. Generation of these probes is therefore desirable to accommodate individual research requirements. Hence, we detail the methodology required to design and produce custom locus-specific interphase FISH probes for any human genomic region of interest and their application was illustrated in cytogenetic investigations of Barrett's tumourigenesis. Previously utilising FISH, we observed that Barrett's tissues demonstrated chromosome 4 hyperploidy [Gut 52 (2003) 623], but as centromeric probes were used in this analysis, it was not known if the whole chromosome was amplified. We consequently generated single-copy sequence probes for the 4p16.3 and 4q35.1 subtelomeric loci. Multicolour FISH was subsequently performed on interphase preparations originating from patients with Barrett's esophagus at varying histological grades, thus demonstrating the whole region of chromosome 4 was amplified within the tissues. Additionally, probes for the DNA methyltransferase genes were produced to determine if gene dosage alterations were responsible for increasing methylation activity during Barrett's neoplastic progression. No significant alterations at the DNMT1 and DNMT3a loci were detected. An increased copy number of these genes is therefore not the basis for the hypermethylation commonly observed in this premalignant lesion.
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PMID:Generation of locus-specific probes for interphase fluorescence in situ hybridisation--application in Barrett's esophagus. 1521 47

ICF syndrome is a rare autosomal recessive disease characterized by variable immunodeficiency, centromeric instability, and facial abnormalities. Mutations in the catalytic domain of DNMT3B, a gene encoding a de novo DNA methyltransferase, have been recognized in a subset of patients. ICF syndrome is a genetic disease directly related to a genomic methylation defect that mainly affects classical satellites 2 and 3, both components of constitutive heterochromatin. The variable incidence of DNMT3B mutations and the differential methylation defect of alpha satellites allow the identification of two types of patients, both showing an undermethylation of classical satellite DNA. This classification illustrates the specificity of the methylation process and raises questions about the genetic heterogeneity of the ICF syndrome.
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PMID:DNMT3B mutations and DNA methylation defect define two types of ICF syndrome. 1558 May 63

The immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome is a rare autosomal recessive disease. Usually, it is caused by mutations in the DNA methyltransferase 3B gene, which result in decreased methylation of satellite DNA in the juxtacentromeric heterochromatin at 1qh, 16qh, and 9qh. Satellite II-rich 1qh and 16qh display high frequencies of abnormalities in mitogen-stimulated ICF lymphocytes without these cells being prone to aneuploidy. Here we show that in lymphoblastoid cell lines from four ICF patients, there was increased colocalization of the hypomethylated 1qh and 16qh sequences in interphase, abnormal looping of pericentromeric DNA sequences at metaphase, formation of bridges at anaphase, chromosome 1 and 16 fragmentation at the telophase-interphase transition, and, in apoptotic cells, micronuclei with overrepresentation of chromosome 1 and 16 material. Another source of anaphase bridging in the ICF cells was random telomeric associations between chromosomes. Our results elucidate the mechanism of formation of ICF chromosome anomalies and suggest that 1qh-16qh associations in interphase can lead to disturbances of mitotic segregation, resulting in micronucleus formation and sometimes apoptosis. This can help explain why specific types of 1qh and 16qh rearrangements are not present at high frequencies in ICF lymphoid cells despite diverse 1qh and 16qh aberrations continuously being generated.
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PMID:Interphase chromosomal abnormalities and mitotic missegregation of hypomethylated sequences in ICF syndrome cells. 1585 60


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