Recapitulation of the Roberts syndrome cellular phenotype by inhibition of INCENP, ZWINT-1 and ZW10 genes

Gene. 2004 Apr 28:331:33-40. doi: 10.1016/j.gene.2004.01.028.


Roberts syndrome is an autosomal recessive disorder characterised primarily by symmetric reduction of all limbs and growth retardation. Patients have been reported to have premature separation of heterochromatin regions of many chromosomes and abnormalities in cell cycle. Given the rarity of the syndrome, the linkage analysis approach is not suitable to identify the responsible gene. In this work, a cell line derived from a patient affected by Roberts syndrome was characterized by cell biology and molecular cytogenetics, including comparative genomic hybridization and spectral karyotype. No recurrent chromosomal rearrangements were identified. Thereafter, based on the fact that premature chromatide separation is a reliable marker of the disease, we used antisense oligonucleotide technologies to inhibit six genes involved in various steps of the correct chromosome segregation, such as chromosome cohesion, kinetochore assembling, spindle checkpoint and spindle formation. We found that the inhibition of INCENP, ZWINT-1, ZW10 genes results in the appearance of mitotic cells characterised by centromere separation, chromosome aneuploidy and micronuclei formation. In addition, INCENP, ZWINT-1, ZW10 antisense-treated chromosome morphology was very similar to that of Roberts chromosome when analysed by atomic force microscopy. We concluded that INCENP, ZWINT-1, ZW10 gene inhibition results in cellular phenocopies of Roberts syndrome. Taken together, these findings support a possible role of these genes in the pathogenesis of Roberts syndrome.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Aneuploidy
  • Caffeine / pharmacology
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Division / drug effects
  • Cell Division / genetics
  • Cell Line
  • Centromere / genetics
  • Centromere / ultrastructure
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosome Aberrations / chemically induced
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation / drug effects
  • Genetic Predisposition to Disease / genetics*
  • Growth Disorders / pathology
  • Humans
  • In Situ Hybridization, Fluorescence
  • Intracellular Signaling Peptides and Proteins
  • Karyotyping / methods
  • Kinetochores / metabolism
  • Limb Deformities, Congenital / pathology
  • Microscopy, Atomic Force
  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • Nucleic Acid Hybridization / methods
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / pharmacology*
  • Phenotype
  • Syndrome


  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • INCENP protein, human
  • Intracellular Signaling Peptides and Proteins
  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • Oligonucleotides, Antisense
  • ZW10 protein, human
  • ZWINT protein, human
  • Caffeine