Variability of clinical and immunological phenotype in immunodeficiency-centromeric instability-facial anomalies syndrome

Franceschini, P; Martino, Silvana; Ciocchini, M.; Ciuti, E; Vardeu, M. P.; Guala, Andrea; Signorile, F.; Camerano, Patrizia; Franceschini, D.; Tovo, Pier-Angelo

doi:10.1007/bf01959794

Cited by 36 publications

(24 citation statements)

References 18 publications

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“…Perhaps the most remarkable characteristic of ICF syndrome is the dramatic elongation of juxtacentromeric heterochromatin in lymphocytes from a ected individuals. Profound chromosomal abnormalities, including multibranched con®gurations (multiradials), deletions or duplications of entire chromosome arms, isochromosomes, and centromeric breakage involving almost exclusively chromosomes 1, 9 and 16 have been observed (Franceschini et al, 1995). Telomeric associations between non-acrocentric chromosomes were also recently reported (Tuck-Muller et al, 2000).…”

Section: Icf Syndromementioning

confidence: 98%

“…A ected individuals demonstrate variable immunode®ciency consisting of an absence or severe reduction in at least two immunoglobulin isotypes and often su er from severe respiratory tract infections (Franceschini et al, 1995;Smeets et al, 1994). Developmental defects include a variable degree of mental impairment, delayed developmental milestones, and peculiar facial features such as low-set ears, hypertelorism,¯at nasal bridge, micrognathia, and macroglossia (Smeets et al, 1994).…”

Section: Icf Syndromementioning

confidence: 99%

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DNA methylation, methyltransferases, and cancer

2001

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The ®eld of epigenetics has recently moved to the forefront of studies relating to diverse processes such as transcriptional regulation, chromatin structure, genome integrity, and tumorigenesis. Recent work has revealed how DNA methylation and chromatin structure are linked at the molecular level and how methylation anomalies play a direct causal role in tumorigenesis and genetic disease. Much new information has also come to light regarding the cellular methylation machinery, known as the DNA methyltransferases, in terms of their roles in mammalian development and the types of proteins they are known to interact with. This information has forced a new view for the role of DNA methyltransferases. Rather than enzymes that act in isolation to copy methylation patterns after replication, the types of interactions discovered thus far indicate that DNA methyltransferases may be components of larger complexes actively involved in transcriptional control and chromatin structure modulation. These new ®ndings will likely enhance our understanding of the myriad roles of DNA methylation in disease as well as point the way to novel therapies to prevent or repair these defects. Oncogene (2001) 20, 3139 ± 3155.

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Section: Icf Syndromementioning

confidence: 98%

Section: Icf Syndromementioning

confidence: 99%

DNA methylation, methyltransferases, and cancer

2001

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“…Most ICF patients are compound heterozygotes for their DNMT3b mutations and, with one exception, all of these mutations occur within the carboxy terminal catalytic domain of DNMT3b and likely fully or partially impair catalytic activity (Robertson, 2001;Xu et al, 1999). Phenotypically, ICF syndrome is characterized by a profound immunodeficiency with an absence or severe reduction in at least two immunoglobulin isotypes, variable impairment in cellular immunity, unusual facial features, neurologic and intestinal dysfunction, and delayed developmental milestones (Franceschini et al, 1995;Smeets et al, 1994).…”

Section: Mbd2 and Mbd3mentioning

confidence: 99%

“…This elongation occurs most consistently on chromosomes 1 and 16, and to a lesser extent chromosome 9. Abnormalities which have been observed include multiradial chromosomes involving multiple arms (3 -12) of one or more of the decondensed chromosomes, whole-arm chromosome deletions or duplications, translocations, centromeric breakage, and in rare cases telomeric associations (Franceschini et al, 1995;Smeets et al, 1994;Tuck-Muller et al, 2000). These observations strongly suggest that defective forms of DNMT3b lead to chromosome instability and large-scale changes in chromatin structure.…”

Section: Mbd2 and Mbd3mentioning

confidence: 99%

DNA methylation and chromatin – unraveling the tangled web

2002

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Methylation of cytosines within the CpG dinucleotide by DNA methyltransferases is involved in regulating transcription and chromatin structure, controlling the spread of parasitic elements, maintaining genome stability in the face of vast amounts of repetitive DNA, and X chromosome inactivation. Cellular DNA methylation is highly compartmentalized over the mammalian genome and this compartmentalization is essential for embryonic development. When the complicated mechanisms that control which DNA sequences become methylated go awry, a number of inherited genetic diseases and cancer may result. Much new information has recently come to light regarding how cellular DNA methylation patterns may be established during development and maintained in somatic cells. Emerging evidence indicates that various chromatin states such as histone modifications (acetylation and methylation) and nucleosome positioning (modulated by ATP-dependent chromatin remodeling machines) determine DNA methylation patterning. Additionally, various regulatory factors interacting with the DNA methyltransferases may direct them to specific DNA sequences, regulate their enzymatic activity, and allow their use as transcriptional repressors. Continued studies of the connections between DNA methylation and chromatin structure and the DNA methyltransferaseassociated proteins, will likely reveal that many, if not all, epigenetic modifications of the genome are directly connected. Such studies should also yield new insights into treating diseases involving aberrant DNA methylation.

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“…Patients present recurrent respiratory infections and diarrhea as consequence of hypogammaglobulinemia or agammaglobulinemia, sometimes associated with defective cell-mediated immunity. 16 Developmental defects such as delayed developmental milestones, facial dismorphy (eg, roundness, hypertelorism, macroglossia), and mental retardation have also been observed. Cytogenetic abnormalities include elongation of centromeric or juxtacentromeric heterochromatin of chromosomes 1, 9, and 16, leading to formation of multiradiate figures involving mainly chromosomes 1 and 16.…”

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confidence: 99%

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

Blanco-Betancourt

Moncla

Milili

et al. 2004

Blood

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IntroductionIn the bone marrow (BM), B-cell differentiation leads to generation of a broad repertoire of antibody-bearing cells in an antigenindependent manner. After ordered rearrangement of the heavy and light chain loci, immature B cells are the first B-cell subset to express a B-cell receptor (BCR), composed of a surface immunoglobulin M (IgM) and the Ig␣/Ig␤ signaling complex (reviewed in Meffre et al 1 ). This process yields a number of potentially self-reactive clones, which can be eliminated by apoptosis (clonal deletion), modified by secondary rearrangements (receptor editing), or rendered hyporesponsive (anergy). [2][3][4][5] In the mouse, 2 ϫ 10 7 immature B cells are generated every day, of which around 90% undergo negative selection. 6 Before migrating to the periphery, immature B cells develop into IgM hi IgD lo CD21 Ϫ CD23 Ϫ type 1 (T1) transitional B cells. 7 They differentiate in the spleen into IgM hi IgD ϩ CD21 ϩ CD23 ϩ type 2 (T2) transitional B cells and then into either IgM hi IgD Ϫ CD21 ϩ CD23 Ϫ marginal zone or IgM lo IgD hi CD21 ϩ CD23 ϩ follicular mature B cells. 8 Both transitional B-cell subsets appear to be short lived (3 to 4 days) 6 and nondividing in vivo, 9 although recent studies show that T2's proliferate and up-regulate survival signals, whereas T1's die after in vitro BCR engagement. 10 Moreover, T1's express CD95 but not the antiapoptotic molecule bcl-2, 7 further suggesting that T1 might be the target of the B-cell-negative selection occurring in the periphery. 11 Such transitional B-cell subsets have not yet been defined in humans. Current characterization of human peripheral blood (PB) B cells is based on the expression of the tumor necrosis factor family member CD27, which distinguishes unmutated IgM ϩ IgD ϩ CD27 Ϫ naive cells (approximately 60% in adults) from somatically hypermutated CD27 ϩ memory cells (40%, of which approximately 40% are IgM ϩ IgD ϩ ). 12 Naive B cells may be the target of negative selection, since heavy chain variable region (V H ) usage as well as the V H complementarity determining region 3 (CDR3) length changes in peripheral mature B cells. [13][14][15] The analysis of primary immune deficiencies is a powerful tool for the study of normal human B-cell differentiation. Immunodeficiency, centromeric region instability, and facial anomalies (ICF) disease is a rare autosomal recessive syndrome, characterized by chromosomal instability and humoral immune deficiency. Patients present recurrent respiratory infections and diarrhea as consequence of hypogammaglobulinemia or agammaglobulinemia, sometimes associated with defective cell-mediated immunity. 16 Developmental defects such as delayed developmental milestones, facial dismorphy (eg, roundness, hypertelorism, macroglossia), and mental retardation have also been observed. Cytogenetic abnormalities include elongation of centromeric or juxtacentromeric heterochromatin of chromosomes 1, 9, and 16, leading to formation of multiradiate figures involving mainly chromosomes 1 and 16. 17 ICF patients show ma...

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Variability of clinical and immunological phenotype in immunodeficiency-centromeric instability-facial anomalies syndrome

Cited by 36 publications

References 18 publications

DNA methylation, methyltransferases, and cancer

DNA methylation, methyltransferases, and cancer

DNA methylation and chromatin – unraveling the tangled web

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

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