title: 3D-FISH analysis reveals chromatid cohesion defect during interphase in Roberts syndrome.
abstract: BACKGROUND
  Roberts syndrome (RBS) is a rare autosomal recessive disorder mainly characterized by growth retardation, limb defects and craniofacial anomalies. Characteristic cytogenetic findings are "railroad track" appearance of chromatids and premature centromere separation in metaphase spreads. Mutations in the ESCO2 (establishment of cohesion 1 homolog 2) gene located in 8p21.1 have been found in several families. ESCO2, a member of the cohesion establishing complex, has a role in the effective cohesion between sister chromatids. In order to analyze sister chromatids topography during interphase, we performed 3D-FISH using pericentromeric heterochromatin probes of chromosomes 1, 4, 9 and 16, on preserved nuclei from a fetus with RBS carrying compound heterozygous null mutations in the ESCO2 gene.
  
  
  RESULTS
  Along with the first observation of an abnormal separation between sister chromatids in heterochromatic regions, we observed a statistically significant change in the intranuclear localization of pericentromeric heterochromatin of chromosome 1 in cells of the fetus compared to normal cells, demonstrating for the first time a modification in the spatial arrangement of chromosome domains during interphase.
  
  
  CONCLUSIONS
  We hypothesize that the disorganization of nuclear architecture may result in multiple gene deregulations, either through disruption of DNA cis interaction -such as modification of chromatin loop formation and gene insulation - mediated by cohesin complex, or by relocation of chromosome territories. These changes may modify interactions between the chromatin and the proteins associated with the inner nuclear membrane or the pore complexes. This model offers a link between the molecular defect in cohesion and the complex phenotypic anomalies observed in RBS.
authors.affiliation: Unité fonctionnelle de Cytogénétique-Département de Génétique- APHP, Hôpital Robert Debré, 48 Bd Sérurier, 75935 Paris, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Dupont
authors.affiliation: Laboratoire de Fœtopathologie- APHP, Hôpital Jean Verdier, Bondy, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Bucourt
authors.affiliation: Service de Biologie du Développement- APHP, Hôpital Robert Debré, Paris, France ; Université Paris Diderot Sorbonne Paris Cité, UMR 1141, F-75019 Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guimiot
authors.affiliation: Unité fonctionnelle de Génétique moléculaire - Département de Génétique- APHP, Hôpital Robert Debré, Paris, France.
authors.forename: Lilia
authors.initials: L
authors.lastname: Kraoua
authors.affiliation: Génomique, Epigénétique et Physiopathologie de la Reproduction, U1016 INSERM-UMR 8104 CNRS (Institut Cochin), Université Paris Descartes, Faculté de Médecine, Paris, France ; Laboratoire de Cytogénétique- APHP, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Smiljkovski
authors.affiliation: Laboratoire de Cytogénétique- APHP, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Le Tessier
authors.affiliation: Institut Cochin, Plateforme d'imagerie cellulaire, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Lebugle
authors.affiliation: Unité fonctionnelle de Génétique moléculaire - Département de Génétique- APHP, Hôpital Robert Debré, Paris, France.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Gerard
authors.affiliation: Service de Biologie du Développement- APHP, Hôpital Robert Debré, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Spaggiari
authors.affiliation: Institut Cochin, Plateforme d'imagerie cellulaire, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bourdoncle
authors.affiliation: Unité fonctionnelle de Cytogénétique-Département de Génétique- APHP, Hôpital Robert Debré, 48 Bd Sérurier, 75935 Paris, France.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Tabet
authors.affiliation: Unité fonctionnelle de Cytogénétique-Département de Génétique- APHP, Hôpital Robert Debré, 48 Bd Sérurier, 75935 Paris, France ; Service d'Histologie, Embryologie et Cytogénétique, Biologie de la Reproduction- APHP, Hôpital Jean Verdier, Bondy, France; UFR-SMBH, Paris, XIII France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Benzacken
authors.affiliation: Génomique, Epigénétique et Physiopathologie de la Reproduction, U1016 INSERM-UMR 8104 CNRS (Institut Cochin), Université Paris Descartes, Faculté de Médecine, Paris, France ; Laboratoire de Cytogénétique- APHP, Hôpitaux Universitaires Paris Centre, Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dupont
keywords: Cohesinopathy; ESCO2; Heterochromatin; Limb development