Abstract
BackgroundRoberts 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.ResultsAlong 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.ConclusionWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-014-0059-6) contains supplementary material, which is available to authorized users.
Highlights
Roberts syndrome (RBS) is a rare autosomal recessive disorder mainly characterized by growth retardation, limb defects and craniofacial anomalies
3D FISH: Behavior of pericentromeric heterochromatin of chromosome 1 in interphase RBS cells Using 3D FISH we showed that approximately 90% of RBS fibroblasts (7/8) and trophoblasts (23/26) nuclei had a split configuration of one or two PH1 signals (Figure 2A)
Cells were counterstained with DAPI. (A) Control cells hybridized with PH1 probe. (B) RBS cells with split signal of one or two territories. (C) Focus on split spots of PH1 showing the bridge between the two signals
Summary
Roberts syndrome (RBS) is a rare autosomal recessive disorder mainly characterized by growth retardation, limb defects and craniofacial anomalies. 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. Roberts Syndrome (RBS, OMIM #268300) is a rare autosomal recessive disorder first described by John Roberts in 1919 This multiple congenital anomaly syndrome is characterized by cleft lip and palate, nose and ears anomalies, facial hemangioma, hypertelorism, microcephaly, curly silvery blond hair, reductional limb defects leading to oligodactyly or tetraphocomelia, polycystic or dysplastic kidneys, congenital heart defects, enlarged male genitalia, severe growth retardation and intellectual prominent in the pericentromeric, heterochromatic regions of chromosomes 1, 9 and 16, in the p arm of acrocentric chromosomes, and in Yq heterochromatin. Abnormal spatial organization of the CTs in interphase was reported in tumor cells carrying chromosome translocations [12], in epilepsy [13], in laminopathies [14], and in ICF syndrome [15,16]
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