Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Mutations in the gene encoding for a de novo methyltransferase, DNMT3B, lead to an autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome. To analyse the protein structure and consequences of ICF-causing mutations, we modelled the structure of the DNMT3B methyltransferase domain based on Haemophilus haemolyticus protein in complex with the cofactor AdoMet and the target DNA sequence. The structural model has a two-subdomain fold where the DNA-binding region is situated between the subdomains on a surface cleft having positive electrostatic potential. The smaller subdomains of the methyltransferases differ in length and sequences and therefore only the target recognition domain loop was modelled to show the location of an ICF-causing mutation. Based on the model, the DNMT3B recognizes the GC sequence and flips the cytosine from the double-stranded DNA to the catalytic pocket. The amino acids in the cofactor and target cytosine binding sites and also the electrostatic properties of the binding pockets are conserved. In addition, a registry of all known ICF-causing mutations, DNMT3Bbase, was constructed. The structural principles of the pathogenic mutations based on the modelled structure and the analysis of chi angle rotation changes of mutated side chains are discussed.
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PMID:Structural basis of ICF-causing mutations in the methyltransferase domain of DNMT3B. 1260 Nov 40

Mutations in the DNMT3B DNA methyltransferase gene cause the ICF immunodeficiency syndrome. The targets of this DNA methyltransferase are CpG-rich heterochromatic regions, including pericentromeric satellites and the inactive X chromosome. The abnormal hypomethylation in ICF cells provides an important model system for determining the relationships between replication time, CpG island methylation, chromatin structure, and gene silencing in X chromosome inactivation.
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PMID:ICF syndrome cells as a model system for studying X chromosome inactivation. 1290 May 41

Only one human disease that involves Mendelian inheritance of immunodeficiency and aberrant DNA methylation has been identified. This is a rare chromosome breakage disease called the immunodeficiency, centromeric region instability, and facial anomalies syndrome (ICF). Its diagnostic characteristics are agammaglobulinemia with B cells as well as DNA rearrangements targeted to the centromere-adjacent heterochromatic region (qh) of chromosomes 1, 16, and sometimes 9 in mitogen-stimulated lymphocytes. These rearrangement-prone regions show DNA hypomethylation in all examined ICF cell populations. This review summarizes our knowledge about the immunological symptoms of ICF; the nature of DNMT3B mutations in ICF patients; the phenotypes of DNA hypomethylation mutants in humans, mice, and Arabidopsis; the epigenetics of ICF; and ICF-specific RNA expression and cell-surface antigen expression in lymphoblastoid cell lines. Comparisons of ICF and control lymphoblastoid cell lines and ICF patients' symptoms suggest an involvement of DNA methylation in the late stages of lymphocyte maturation.
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PMID:The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. 1458 72

We report on a patient affected by ICF syndrome (immunodeficiency, centromeric instability of chromosomes 1, 9 and 16 and facial dysmorphism), who presented with slowing in mentation, mild right hemiparesis and focal motor seizures. MRI study of the brain suggested a diagnosis of progressive multifocal leukoencephalopathy (PML), which was confirmed by JC virus DNA detection on CSF by polymerase chain reaction (PCR). This is a unique case of adult infective neurological complication described in ICF Syndrome.
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PMID:Progressive multifocal leukoencephalopathy in an adult patient with ICF syndrome. 1467 17

DNA methylation patterns of mammalian genomes are generated in gametogenesis and early embryonic development. Two de novo DNA methyltransferases, Dnmt3a and Dnmt3b, are responsible for the process. Both enzymes contain a long N-terminal regulatory region linked to a conserved C-terminal domain responsible for the catalytic activity. Although a PWWP domain in the N-terminal region has been shown to bind DNA in vitro, it is unclear how the DNA methyltransferases access their substrate in chromatin in vivo. We show here that the two proteins are associated with chromatin including mitotic chromosomes in mammalian cells, and the PWWP domain is essential for the chromatin targeting of the enzymes. The functional significance of PWWP-mediated chromatin targeting is suggested by the fact that a missense mutation in this domain of human DNMT3B causes immunodeficiency, centromeric heterochromatin instability, facial anomalies (ICF) syndrome, which is characterized by loss of methylation in satellite DNA, pericentromeric instability, and immunodeficiency. We demonstrate that the mutant protein completely loses its chromatin targeting capacity. Our data establish the PWWP domain as a novel chromatin/chromosome-targeting module and suggest that the PWWP-mediated chromatin association is essential for the function of the de novo methyltransferases during development.
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PMID:Chromatin targeting of de novo DNA methyltransferases by the PWWP domain. 1499 98

Proper patterns of genome-wide DNA methylation, mediated by DNA methyltransferases DNMT1, -3A and -3B, are essential for embryonic development and genomic stability in mammalian cells. The de novo DNA methyltransferase DNMT3B is of particular interest because it is frequently overexpressed in tumor cells and is mutated in immunodeficiency, centromere instability and facial anomalies (ICF) syndrome. In order to gain a better understanding of DNMT3B, in terms of the targeting of its methylation activity and its role in genome stability, we biochemically purified endogenous DNMT3B from HeLa cells. DNMT3B co-purifies and interacts, both in vivo and in vitro, with several components of the condensin complex (hCAP-C, hCAP-E and hCAP-G) and KIF4A. Condensin mediates genome-wide chromosome condensation at the onset of mitosis and is critical for proper segregation of sister chromatids. KIF4A is proposed to be a motor protein carrying DNA as cargo. DNMT3B also interacts with histone deacetylase 1 (HDAC1), the co-repressor SIN3A and the ATP-dependent chromatin remodeling enzyme hSNF2H. Further more, DNMT3B co-localizes with condensin and KIF4A on condensed chromosomes throughout mitosis. These studies therefore reveal the first direct link between the machineries regulating DNA methylation and mitotic chromosome condensation in mammalian cells.
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PMID:Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery. 1514 59

The Immunodeficiency, Centromeric instability, and Facial (ICF) syndrome is a rare autosomal recessive disorder that results from mutations in the DNMT3B gene, encoding a DNA-methyltransferase that acts on GC-rich satellite DNAs. This syndrome is characterized by immunodeficiency, facial dysmorphy, mental retardation of variable severity and chromosomal abnormalities that essentially involve juxtacentromeric heterochromatin of chromosomes 1 and 16. These abnormalities demonstrate that hypomethylation of satellite DNA can induce alterations in the structure of heterochromatin. In order to investigate the effect of DNA hypomethylation on heterochromatin organization, we analyzed the in vivo distribution of HP1 proteins, essential components of heterochromatin, in three ICF patients. We observed that, in a large proportion of ICF G2 nuclei, all HP1 isoforms show an aberrant signal concentrated into a prominent bright focus that co-localizes with the undercondensed 1qh or 16qh heterochromatin. We found that SP100, SUMO-1 and other proteins from the promyelocytic leukemia nuclear bodies (NBs) form a large body that co-localizes with the HP1 signal. This is the first description of altered nuclear distribution of HP1 proteins in the constitutional ICF syndrome. Our results show that satellite DNA hypomethylation does not prevent HP1 proteins from associating with heterochromatin. They suggest that, at G2 phase, HP1 proteins are involved in the heterochromatin condensation and may therefore remain concentrated at these sites until the condensation is complete. They also indicate that proteins from the NB could play a role in this process. Finally, satellite DNA length polymorphism could affect the efficiency of heterochromatin condensation and thus contribute to the variability of the ICF phenotype.
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PMID:Subcellular distribution of HP1 proteins is altered in ICF syndrome. 1547 Mar 59

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


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