Defective B-cell-negative selection and terminal differentiation in the ICF syndrome

Blanco-Betancourt, Carla; Moncla, Anne; Milili, Michèle; Jiang, Ying; Viegas‐Péquignot, Evani; Roquelaure, Bertrand; Thuret, Isabelle; Schiff, Claudine

doi:10.1182/blood-2003-08-2632

Cited by 75 publications

(63 citation statements)

References 58 publications

(93 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A similar association between 1qh/16qh instability and MN formation was observed in the present study. ICF lymphocytes exhibit an increased sensitivity to B-cell apoptosis after in vitro stimulation (Blanco-Betancourt et al 2004). They are also abnormally prone to apoptosis and non-apoptotic cell death following radiation-induced chromosome breakage .…”

Section: Icf Chromosome Damage and Apoptosismentioning

confidence: 99%

“…Immunologically, ICF patients show hypogammaglobulinaemia but with B-cells present (Ehrlich 2003). It has been suggested that this condition is mediated by the dysregulation of lymphogenesis genes (Ehrlich et al 2001) and defective B-cell differentiation, leading to the accumulation of immature B-cells with an increased rate of apoptosis upon in vitro activation (Blanco-Betancourt et al 2004). Because of a strong predisposition for systemic infectious diseases, the majority of ICF patients die before reaching their teens.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Interphase chromosomal abnormalities and mitotic missegregation of hypomethylated sequences in ICF syndrome cells

et al. 2005

View full text Add to dashboard Cite

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.

show abstract

Section: Icf Chromosome Damage and Apoptosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interphase chromosomal abnormalities and mitotic missegregation of hypomethylated sequences in ICF syndrome cells

et al. 2005

View full text Add to dashboard Cite

show abstract

“…2 Studies on T-cell function are limited, and reported data suggest a normal proliferative response upon mitogenic stimulation, the capability to support Pokeweed mitogen (PWM)-induced immunoglobulin production by control B-cells and a somewhat increased degree of apoptosis. 3,4 Therefore, the relative contribution of an intrinsic B-cell defect and a defective T-cell function to the frequently observed dysgammaglobulinemia in patients with ICF syndrome remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

“…Targeted deletion of either the maintenance Dnmt or the de novo Dnmt genes in mouse demonstrated that Dnmts are essential for proper embryonic development [11][12][13]. Mutations in the Dnmt3b gene in human cause a rare autosomal disease, called ICF (immunodeficiency, centromere instability, facial abnormalities) syndrome, with some B-cell specific aspects that include defective B-cell-negative selection and terminal differentiation [14][15][16]. ICF missense mutations in the Dnmt3b gene in mice resulted in similar phenotypes as in human ICF patients [17].…”

Section: Introductionmentioning

confidence: 99%

De novo DNA Methyltransferases Dnmt3a and Dnmt3b regulate the onset of Igκ light chain rearrangement during early B‐cell development

et al. 2015

View full text Add to dashboard Cite

Immunoglobulin genes V(D)J rearrangement during early lymphopoiesis is a critical process involving sequential recombination of the heavy and light chain loci. A number of transcription factors act together with temporally activated recombinases and chromatin accessibility changes to regulate this complex process. Here, we deleted the de novo DNA methyltransferases Dnmt3a and Dnmt3b in early B cells of conditionally targeted mice, and monitored the process of V(D)J recombination. Dnmt3a and Dnmt3b deletion resulted in precocious recombination of the immunoglobulin κ light chain without impairing the differentiation of mature B cells or overall B-cell development. Ex vivo culture of IL-7 restricted early B-cell progenitors lacking Dnmt3a and Dnmt3b showed precocious Vκ-Jκ rearrangements that are limited to the proximal Vκ genes. Furthermore, B-cell progenitors deficient in Dnmt3a and Dnmt3b showed elevated levels of germline transcripts at the proximal Vκ genes, alterations in methylation patterns at Igκ enhancer sites and increased expression of the transcription factor E2A. Our data suggest that Dnmt3a and Dnmt3b are critical to regulate the onset of Igκ light chain rearrangement during early B-cell development.Keywords: B-cell r DNA methylation r Immunoglobulin r V(D)J rearrangement Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe development of lymphocytes (B or T cells) through differentiation of HSCs into several successive progenitor stages involves highly coordinated events orchestrated by many different genes, which often act at specific stages of cell differentiation. These genes encode lineage-specific transcription factors, growth factors, and chemokines and their receptors [1][2][3][4]. The primary function Correspondence: Prof. Patrick Matthias e-mail: patrick.matthias@fmi.ch of B lymphocyte is to produce high level of antigen-specific antibodies. To generate a very large repertoire of antigen receptors (antibodies) early B cells undergo a somatic recombination process known as V(D)J recombination that assembles variable (V), diversity (D), and joining (J) gene segments of the immunoglobulin (Ig) locus to create a large diversity of antibodies [5,6].The mouse Ig heavy (IgH) and light (IgL) chain (κ or λ) loci become activated during B-cell development in a step-wise manner for V(D)J recombination. Eur. J. Immunol. 2015Immunol. . 45: 2343Immunol. -2355 the small pre-BII cell stage, thereby giving rise to functional Ig genes in successive stages of B-cell development [6,7]. The V(D)J recombinase proteins Rag-1 and Rag-2 are responsible for the induction of cleavage and recombination at conserved flanking regions (recombination signal sequences, RSS) of the V, D, and J gene segments within the Ig loci. Accessibility of RSS sites at the Ig locus for Rag-1 and Rag-2 mediated synapsis and cleavage is dependent on chromatin structure and epigenetic marks [7][8][9]. DNA methylation is a covalent modification of the genomic DNA...

show abstract

Defective B-cell-negative selection and terminal differentiation in the ICF syndrome

Cited by 75 publications

References 58 publications

Interphase chromosomal abnormalities and mitotic missegregation of hypomethylated sequences in ICF syndrome cells

Interphase chromosomal abnormalities and mitotic missegregation of hypomethylated sequences in ICF syndrome cells

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

De novo DNA Methyltransferases Dnmt3a and Dnmt3b regulate the onset of Igκ light chain rearrangement during early B‐cell development

Contact Info

Product

Resources

About