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1.
Jiang YL Rigolet M Bourc'his D Nigon F Bokesoy I Fryns JP Hultén M Jonveaux P Maraschio P Mégarbané A Moncla A Viegas-Péquignot E 《Human mutation》2005,25(1):56-63
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. 相似文献
2.
A novel deletion in ZBTB24 in a Lebanese family with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 总被引:1,自引:0,他引:1
Chouery E Abou-Ghoch J Corbani S El Ali N Korban R Salem N Castro C Klayme S Azoury-Abou Rjeily M Khoury-Matar R Debo G Germanos-Haddad M Delague V Lefranc G Mégarbané A 《Clinical genetics》2012,82(5):489-493
3.
Dupont C Guimiot F Perrin L Marey I Smiljkovski D Le Tessier D Lebugle C Baumann C Bourdoncle P Tabet AC Aboura A Benzacken B Dupont JM 《Clinical genetics》2012,82(2):187-192
ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome is a rare autosomal recessive disorder characterised by severe immunodeficiency, craniofacial anomalies and chromosome instability. Chromosome analyses from blood samples show a high frequency of decondensation of pericentromeric heterochromatin (PH) and rearrangements involving chromosomes 1 and 16. It is the first and, as far as we know, the only disease associated with a mutation in a DNA methyltransferase gene, DNMT3B, with significant hypomethylation of the classical satellite DNA, the major component of the juxtacentromeric heterochromatin. To better understand the complex links between the hypomethylation of the satellite DNA, the cytogenetic anomalies and the clinical features of ICF syndrome, we performed three-dimensional (3D) FISH on preserved cells from a patient with a suspected ICF phenotype. Analysis of DNMT3B did not reveal any mutation in our patient, making this case an ICF type 2. The results of 3D-FISH showed a statistically significant change in the intranuclear position of PH of chromosome 1 in cells of the patient as compared to normal cells. It is difficult to understand how a defect in the methylation pathway can be responsible for the various symptoms of this condition. From our observations we suggest a mechanistic link between the reorganisation of the nuclear architecture and the altered gene expression. 相似文献
4.
The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease 总被引:9,自引:0,他引:9
Ehrlich M 《Clinical immunology (Orlando, Fla.)》2003,109(1):17-28
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. 相似文献
5.
Corry MR Weemaes Maarten JD van Tol Jun Wang Monique M van Ostaijen-ten Dam Marja CJA van Eggermond Peter E Thijssen Caner Aytekin Nicola Brunetti-Pierri Mirjam van der Burg E Graham Davies Alina Ferster Dieter Furthner Giorgio Gimelli Andy Gennery Barbara Kloeckener-Gruissem Stephan Meyn Cynthia Powell Ismail Reisli Catharina Schuetz Ansgar Schulz Andrea Shugar Peter J van den Elsen Silvère M van der Maarel 《European journal of human genetics : EJHG》2013,21(11):1219-1225
Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype–phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling. 相似文献
6.
Xie ZH Huang YN Chen ZX Riggs AD Ding JP Gowher H Jeltsch A Sasaki H Hata K Xu GL 《Human molecular genetics》2006,15(9):1375-1385
Deficiency in DNA methyltransferase DNMT3B causes a recessive human disorder characterized by immunodeficiency, centromeric instability and facial anomalies (ICF) in association with defects in genomic methylation. The majority of ICF mutations are single amino acid substitutions in the conserved catalytic domain of DNMT3B, which are believed to impair its enzymatic activity directly. The establishment of intact genomic methylation patterns in development requires a fine regulation of the de novo methylation activity of the two related methyltransferases DNMT3A and DNMT3B by regulatory factors including DNMT3L which has a stimulatory effect. Here, we show that two DNMT3B mutant proteins with ICF-causing substitution (A766P and R840Q) displayed a methylation activity similar to the wild-type enzyme both in vitro and in vivo. However, their stimulation by DNMT3L was severely compromised due to deficient protein interaction. Our findings suggest that methylation defects in ICF syndrome may also result from impaired stimulation of DNMT3B activity by DNMT3L or other unknown regulatory factors as well as from a weakened basal catalytic activity of the mutant DNMT3B protein per se. 相似文献
7.
8.
Wijmenga C Hansen RS Gimelli G Björck EJ Davies EG Valentine D Belohradsky BH van Dongen JJ Smeets DF van den Heuvel LP Luyten JA Strengman E Weemaes C Pearson PL 《Human mutation》2000,16(6):509-517
ICF syndrome is a rare autosomal recessive immunoglobulin deficiency, sometimes combined with defective cellular immunity. Other features that are frequently observed in ICF syndrome patients include facial dysmorphism, developmental delay, and recurrent infections. The most diagnostic feature of ICF syndrome is the branching of chromosomes 1, 9, and 16 due to pericentromeric instability. Positional candidate cloning recently discovered the de novo DNA methyltransferase 3B (DNMT3B) as the responsible gene by identifying seven different mutations in nine ICF patients. DNMT3B specifically methylates repeat sequences adjacent to the centromeres of chromosome 1, 9, and 16. Our panel of 14 ICF patients was subjected to mutation analysis in the DNMT3B gene. Mutations in DNMT3B were discovered in only nine of our 14 ICF patients. Moreover, two ICF patients from consanguineous families who did not show autozygosity (i.e. homozygosity by descent) for the DNMT3B locus did not reveal DNMT3B mutations, suggesting genetic heterogeneity for this disease. Mutation analysis revealed 11 different mutations, including seven novel ones: eight different missense mutations, two different nonsense mutations, and a splice-site mutation leading to the insertion of three aa's. The missense mutations occurred in or near the catalytic domain of DNMT3B protein, indicating a possible interference with the normal functioning of the enzyme. However, none of the ICF patients was homozygous for a nonsense allele, suggesting that absence of this enzyme is not compatible with life. Compound heterozygosity for a missense and a nonsense mutation did not seem to correlate with a more severe phenotype. 相似文献
9.
10.
Defective de novo methylation of viral and cellular DNA sequences in ICF syndrome cells 总被引:1,自引:0,他引:1
Tao Q Huang H Geiman TM Lim CY Fu L Qiu GH Robertson KD 《Human molecular genetics》2002,11(18):2091-2102
ICF syndrome (immunodeficiency, centromere instability and facial anomalies) is a recessive human genetic disorder resulting from mutations in the DNA methyltransferase 3B (DNMT3B) gene. Patients with this disease exhibit numerous chromosomal abnormalities, including anomalous decondensation, pairing, separation and breakage, primarily involving the pericentromeric regions of chromosomes 1 and 16. Global levels of DNA methylation in ICF cells are only slightly reduced; however, certain repetitive sequences and genes on the inactive X chromosome of female ICF patients are significantly hypomethylated. In the present report, we analyze the molecular defect of de novo methylation in ICF cells in greater detail by making use of a model Epstein-Barr virus (EBV)-based system and three members of the unique cellular cancer-testis (C-T) gene family. Results with the EBV-based system indicate that de novo methylation of newly introduced viral sequences is defective in ICF syndrome. Limited de novo methylation capacity is retained in ICF cells, indicating that the mutations in DNMT3B are not complete loss-of-function mutations or that other DNMTs cooperate with DNMT3B. Analysis of three C-T genes (two on the X chromosome and one autosomal) revealed that loss of methylation from cellular gene sequences is heterogeneous, with both autosomal and X chromosome-based genes demonstrating sensitivity to mutations in DNMT3B. Aberrant hypomethylation at a number of loci examined correlated with altered gene expression levels. Lastly, no consistent changes in the protein levels of the DNA methyltransferases were noted when normal and ICF cell lines were compared. 相似文献
11.
Kaya N Al-Muhsen S Al-Saud B Al-Bakheet A Colak D Al-Ghonaium A Al-Dhekri H Al-Mousa H Arnaout R Al-Owain M Iqbal M 《Journal of clinical immunology》2011,31(2):245-252
Background
Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is an extremely rare autosomal recessive disorder. In addition to the juxtacentromeric heterochromatic instability, the disease is characterized by variable reduction in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood as well as exhibit facial dysmorphism including hypertelorism, epicanthal folds, and low-set ears.Subjects and Methods
A case series of five patients with ICF from a major immunodeficiency center in Saudi Arabia were included. Immunological and cytogenetic studies were performed for all the five patients. Molecular data was conducted on three patients.Results
All patients had variable hypogammaglobulinemia and characteristic centromeric instability of chromosomes 1, 16, and sometimes 9. One of the patients had pseudomonas meningitis. Pauciarticular arthritis was noted in one patient, a previously not reported finding in ICF, though it has been reported among patients with humoral immune defect. In addition, we identified a novel homozygous c.2506 G>A (p.V836M) mutation in DNMT3B in one of the three patients tested.Conclusions
This report describes five patients with ICF Saudi Arabia for the first time. ICF should be suspected in children with facial dysmorphism who present with recurrent infections especially in highly inbred populations. 相似文献12.
DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes. 总被引:7,自引:0,他引:7
M Ehrlich K L Buchanan F Tsien G Jiang B Sun W Uicker C M Weemaes D Smeets K Sperling B H Belohradsky N Tommerup D E Misek J M Rouillard R Kuick S M Hanash 《Human molecular genetics》2001,10(25):2917-2931
13.
Whole-genome methylation scan in ICF syndrome: hypomethylation of non-satellite DNA repeats D4Z4 and NBL2 总被引:8,自引:0,他引:8
Kondo T Bobek MP Kuick R Lamb B Zhu X Narayan A Bourc'his D Viegas-Péquignot E Ehrlich M Hanash SM 《Human molecular genetics》2000,9(4):597-604
The ICF (immunodeficiency, centromeric instability and facial abnormalities) syndrome is a rare recessive disease characterized by immunodeficiency, extraordinary instability of certain heterochromatin regions and mutations in the gene encoding DNA methyltransferase 3B. In this syndrome, chromosomes 1 and 16 are demethylated in their centromere-adjacent (juxtacentromeric) heterochromatin, the same regions that are highly unstable in mitogen-treated ICF lymphocytes and B cell lines. We investigated the methylation abnormalities in CpG islands of B cell lines from four ICF patients and their unaffected parents. Genomic DNA digested with a CpG methylation-sensitive restriction enzyme was subjected to two-dimensional gel electrophoresis. Most of the restriction fragments were identical in the digests from the patients and controls, indicating that the methylation abnormality in ICF is restricted to a small portion of the genome. However, ICF DNA digests prominently displayed multicopy fragments absent in controls. We cloned and sequenced several of the affected DNA fragments and found that the non-satellite repeats D4Z4 and NBL2 were strongly hypomethylated in all four patients, as compared with their unaffected parents. The high degree of methylation of D4Z4 that we observed in normal cells may be related to the postulated role of this DNA repeat in position effect variegation in facio- scapulohumeral muscular dystrophy and might also pertain to abnormal gene expression in ICF. In addition, our finding of consistent hypomethylation and overexpression of NBL2 repeats in ICF samples suggests derangement of methylation-regulated expression of this sequence in the ICF syndrome. 相似文献
14.
15.
Multibranched chromosomes in the ICF syndrome: immunodeficiency, centromeric instability, and facial anomalies 总被引:6,自引:0,他引:6
C Turleau M O Cabanis D Girault F Ledeist R Mettey H Puissant M Prieur J de Grouchy 《American journal of medical genetics》1989,32(3):420-424
A new patient with the rare ICF syndrome (immunodeficiency, centromeric heterochromatin instability, and facial anomalies) is reported. The six patients previously reported in the literature are reviewed. The main clinical and cytogenetic characteristics of the syndrome are discussed. 相似文献
16.
De Bonis ML Cerase A Matarazzo MR Ferraro M Strazzullo M Hansen RS Chiurazzi P Neri G D'Esposito M 《Human molecular genetics》2006,15(7):1123-1132
Maintenance of X-inactivation is achieved through a combination of different repressive mechanisms, thus perpetuating the silencing message through many cell generations. The second human X-Y pseudoautosomal region 2 (PAR2) is a useful model to explore the features and internal relationships of the epigenetic circuits involved in this phenomenon. Recently, we demonstrated that DNA methylation plays an essential role for the maintenance of X- and Y-inactivation of the PAR2 gene SYBL1; here we report that the silencing of the second repressed PAR2 gene, SPRY3, appears to be independent of DNA methylation. In contrast to SYBL1, the inactive X and Y alleles of SPRY3 are not reactivated in cells treated with a DNA methylation inhibitor and in cells from ICF (immunodeficiency, centromeric instability, facial anomalies) syndrome patients, which have mutations in the DNA methyltransferase gene DNMT3B. SPRY3 X- and Y-inactivation is associated with a differential enrichment of repressive histone modifications and the recruitment of Polycomb 2 group proteins compared to the active X allele. Another major factor in SPRY3 repression is late replication; the inactive X and Y alleles of SPRY3 have delayed replication relative to the active X allele, even in ICF syndrome cells where the closely linked SYBL1 gene is reactivated and advanced in replication. The relatively stable maintenance of SPRY3 silencing compared with SYBL1 suggests that genes without CpG islands may be less prone to reactivation than previously thought and that genes with CpG islands require promoter methylation as an additional layer of repression. 相似文献
17.
M Cerbone J Wang SM Van der Maarel A D'Amico A D'Agostino A Romano N Brunetti-Pierri 《American journal of medical genetics. Part A》2012,(8):2043-2046
The immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is an autosomal recessive disease presenting with immunodeficiency secondary to hypo- or agamma-globulinemia, developmental delay, and facial anomalies. Centromeric instability is the cytogenetic hallmark of the disorder which results from targeted chromosomal rearrangements related to a genomic methylation defect. We describe a patient carrying a homozygous mutation of the ZBTB24 gene, which has been recently shown to be responsible for ICF syndrome type 2. Our patient presented with intellectual disability, multiple café-au-lait spots, and a large cerebral arachnoidal cyst. Although laboratory signs of impaired immune function, such as reduced serum IgM were detected, our patient did not present clinical manifestations of immunodeficiency. Brain malformations abnormalities have not been reported so far in ICF syndrome and it can be speculated that ZBTB24 mutations may alter cerebral development. Nevertheless, we cannot rule out that the presence of the cerebral cyst in the patient is coincidental. In summary, our patient illustrates that clinical evidence of immunodeficiency is not a universal feature of ICF2 syndrome type 2 and suggests that brain malformations may be present in other ICF cases. 相似文献
18.
Park J Kim TY Jung Y Song SH Kim SH Oh DY Im SA Bang YJ 《Journal of molecular medicine (Berlin, Germany)》2008,86(11):1269-1277
Mutations of the DNA methyltransferase 3B (DNMT3B) gene have been detected in patients with immunodeficiency, centromere instability,
and facial anomalies (ICF) syndrome. Most of these mutations are clustered in its catalytic domain and thus lead to defective
DNA methylation. Nevertheless, the S270P mutation in the N-terminal PWWP (Pro-Trp-Trp-Pro) domain of the DNMT3B gene has prompted
questions as to how this mutation contributes to the development of ICF syndrome. In this study, we found that wild-type DNMT3B
is SUMOylated through covalent modification, whereas the S270P mutant interacts with SUMO-1 via non-covalent interaction.
The S270P mutation results in diffuse nucleus localization. Moreover, the S270P mutant fails to interact with PIAS1, a small
ubiquitin-related modifier (SUMO) E3 ligase, and causes the constitutive activation of nuclear factor-kappa B, which induces
the expression of interleukin 8. Collectively, our data demonstrate that the S270P mutation affects DNMT3B functions via specific,
non-covalent interaction with SUMO-1.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
19.
20.
Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies: the ICF syndrome. 总被引:4,自引:1,他引:4
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Instability of the heterochromatic centromeric regions of chromosomes 1, 9, and 16 associated with immunodeficiency was found in a four year old girl. Similar phenotypic and chromosomal abnormalities were described in a previous patient studied by us and in four other published cases. All these patients have facial anomalies in addition to combined immunodeficiency and chromosomal instability. Stretching of the heterochromatic centromeric regions of chromosomes 1, 16, and to a lesser extent, 9 and homologous and non-homologous associations of these regions were the most common cytogenetic findings in all the patients. Multi-branched configurations and whole arm deletions of chromosomes 1 or 16 or both were also found. Comparing clinical and chromosomal data we conclude that immunodeficiency, centromeric heterochromatin instability, and facial anomalies form a new syndrome, for which we propose the acronym ICF. A mutation interfering with the normal process of condensation of part of the centromeric heterochromatin is postulated as the basic chromosome defect in this syndrome. 相似文献