title: 3D position of pericentromeric heterochromatin within the nucleus of a patient with ICF syndrome.
abstract: 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.
authors.affiliation: Institut Cochin, Inserm U567-UMR CNRS 8104 équipe 21, Université Paris Descartes, Faculté de médecine, Paris, France. celine.dupont@jvr.aphp.fr
authors.forename: C
authors.initials: C
authors.lastname: Dupont
authors.forename: F
authors.initials: F
authors.lastname: Guimiot
authors.forename: L
authors.initials: L
authors.lastname: Perrin
authors.forename: I
authors.initials: I
authors.lastname: Marey
authors.forename: D
authors.initials: D
authors.lastname: Smiljkovski
authors.forename: D
authors.initials: D
authors.lastname: Le Tessier
authors.forename: C
authors.initials: C
authors.lastname: Lebugle
authors.forename: C
authors.initials: C
authors.lastname: Baumann
authors.forename: P
authors.initials: P
authors.lastname: Bourdoncle
authors.forename: A-C
authors.initials: AC
authors.lastname: Tabet
authors.forename: A
authors.initials: A
authors.lastname: Aboura
authors.forename: B
authors.initials: B
authors.lastname: Benzacken
authors.forename: J-M
authors.initials: JM
authors.lastname: Dupont
mesh_terms: D000293:Adolescent; D002467:Cell Nucleus / Q000235:genetics*; D002503:Centromere; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1; D002899:Chromosomes, Human, Pair 9; D019175:DNA Methylation; D004276:DNA, Satellite; D005145:Face / Q000002:abnormalities; D005260:Female; D006570:Heterochromatin / Q000737:chemistry*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis* / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D000081207:Primary Immunodeficiency Diseases
chemical_list: D004276:DNA, Satellite; D006570:Heterochromatin