Abstract
Roberts syndrome is an inherited human condition that is of particular interest because separation of centromeres and constitutive heterochromatin is observed in metaphase chromosomes. In this study we investigated the frequency of other cytological abnormalities in three Roberts syndrome patients. Our findings when taken with previous cytological reports emphasize that there are other features that are equally characteristic of Roberts syndrome: (1) aneuploidy with random chromosome loss and (2) micronuclei and/or nuclear lobulations of 8%–24% of interphase cells. We observed abnormal chromosome movement involving one or all the chromosomes during anaphase. Evidence is presented suggesting that aneuploidy, micronuclei and abnormal nuclear morphology are a direct result of lagging chromosomes. The cytological features documented for Roberts syndrome indicate that this is a human mitotic mutant.
Similar content being viewed by others
References
Brinkley BR, Cox SM, Pepper DA, Wible L, Brenner SL, Pardue RL (1981) Tubulin assembly sites and the organization of cytoplasmic microtubules in cultured mammalian cells. J Cell Biol 90: 554–562
Byers B, Goetsch L (1974) Duplication of spindle plaques and integration of the yeast cell cycle. In: Chromosome structure and function, vol. 38. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp 123–131
Chamla Y (1984) C-anaphases in lymphocyte cultures versus premature centromere division syndromes. Hum Genet 78: 111–114
da Silva EO, Bezerra L (1982) The Roberts syndrome. Hum Genet 61: 372–374
Davis BK (1971) Genetic analysis of a meiotic mutant resulting in precocious sister-centromere separation in Drosophila melangoaster. Mol Gen Genet 113: 251–272
Dedman JR, Lin T, Marcum JM, Brinkley BR, Means AR (1980) Calmodulin: Its role in the mitotic apparatus. In: Siegel FL, Carafoli E, Kretsinger RH, MacLennen DH, Waserman RH (eds) Calcium binding proteins; structure and function. Elsevier-North Holland, Amsterdam, pp 181–188
Dev VG, Wertelecki W (1984) Elimination of abnormal centromere-chromatid apposition (ACCA) in selected human-mouse cell hybrids. Am J Hum Genet 36:90S
Draetta G, Beach D (1988) Activation of cdc2 protein kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement. Cell 54: 17–26
Earnshaw WC, Sullivan KF, Machlin PS, Cooke CA, Kaiser DA, Pollard TD, Rothfield NF, Cleveland DW (1987) Molecular cloning of cDNA for CENP-B, the major human centromere autoantigen. J Cell Biol 104: 817–829
Endow SA, Henikoff S, Soler-Niedziela L (1990) Mediation of meiotic and early mitotic chromosome segregation in Drosophila by a protein related to kinesin. Nature 345: 81–83
Epstein CJ, Cox DR, Schonberg SA, Hogge WA (1983) Recent developments in the prenatal diagnosis of genetic diseases and birth defects. Annu Rev Genet 17: 49–83
Freeman MVR, Williams DW, Schimke RN, Temtamy SA, Vachier E, German J (1974) The Roberts syndrome. Birth Defects 10: 87–95
Fuscoe JC, Clark IL, Van Dilla MA (1986) Construction of fifteen human chromosome-specific DNA libraries from flow-purified chromosomes. Cytogenet Cell Genet 43: 79–86
Gatti M, Baker BS (1989) Genes controlling essential cell-cycle functions in Drosophila melanogaster. Genes Dev 3: 438–453
German J (1979) Roberts' syndrome. I. Cytological evidence for a disturbance in chromatid pairing. Clin Genet 16: 441–447
Gethman RC (1984) The genetic analysis of a chromosome-specific meiotic mutant that permits a premature separation of sister chromatids in Drosophila melanogaster. Genetics 107: 65–77
Goldstein LSB (1980) Mechanisms of chromosome orientation revealed by two meiotic mutants in Drosophila melanogaster. Chromosoma 78: 79–111
Gomez MR, Brena EP, Sanchez CL, de Buitrago AG, Eusebio BG, Gonzalez AS, Dominguez MAP, Basurto CV (1982) Sindrome de hipomelia, hypotricosis y hemangioma facial (sindrome pseudothalidomidico). An Esp Pediatr 17: 229–233
Gorbsky GJ, Sammak PJ, Borisy GG (1987) Chromosomes move poleward in anaphase along stationary microtubules that coordinately disassemble from their kinetochore ends. J Cell Biol 104: 9–18
Grosse FR, Pandel C, Wiedemann HR (1975) The tetraphocomelia-cleft palate syndrome. Hum Genet 28: 353–356
Gunby JL, Tomkins DJ, Chang PL (1987) Somatic cell hybridization of Roberts syndrome and normal human fibroblasts transfected with plasmids carrying dominant selection markers. Somatic Cell Mol Genet 13: 245–252
Hall BD, Greenberg MH (1972) Hypomelia-hypotrichosis-facial hemangioma syndrome. Am J Dis Child 123: 602–604
Hermann J, Opitz JM (1977) The SC phocomelia and the Roberts syndrome: nosologic aspects. Eur J of Pediatr 125: 117–134
Hsu LYF, Perlis TE (1984) United States survey on chromosome mosaicism and pseudomosaicism in prenatal diagnosis. Prenat Diagn 4: 97–130
Hsu TC, Satya-Prakash KL (1985) Aneuploidy induction by mitotic arrestants in animal cell systems: possible mechanisms. In: Dcllarco VL, Voytek PE (eds) Aneuploidy: etiology and mechanisms. Plenum Press, New York, pp 279–290
Hunter AGW, Cox DW, Rudd NL (1976) The genetics of and associated clinical findings in humero-radial synostosis. Clin Genet 9: 470–478
Jabs EW, Wolf SF, Migeon BR (1984) Characterization of a cloned DNA sequence that is present at centromeres of all human autosomes and the X chromosome and shows polymorphic variation. Proc Natl Acad Sci USA 81: 4884–4888
Jabs EW, Tuck-Muller CM, Cusano R, Rattner JB (1989a) Centromere separation and aneuploidy in human mitotic mutants: Roberts syndrome. In: Resnick M, Vig B (eds) Mechanisms of chromosome distribution and aneuploidy. Alan R Liss, New York, pp 111–118
Jabs EW, Goble CA, Cutting GR (1989b) The macromolecular organization of human centromeric regions reveals high frequency, polymorphic macro-DNA repeats. Proc Natl Acad Sci USA 86: 202–206
Judge C (1973) A sibship with the pseudothalidomide syndrome and an association with Rh incompatibility. Med J Aust 2: 280–281
Kingwell B, Rattner JB (1987) Mammalian kinetochore/centromere composition: A 50 kDa antigen is present in the mammalian kinetochore/centromere. Chromosoma 95: 403–407
Kirschner M, Mitchison T (1986) Beyond self-assembly: from microtubules to morphogenesis. Cell 45: 329–342
Knoll JH, Ray M, Davies D (1983) Effects of co-cultivation on heterochromatin puffing in Roberts syndrome. Genet Soc Can Bull 14:37 A
Koshland DE, Mitchison TJ, Kirschner MW (1988) Polewards chromosome movement driven by microtubule depolymerization in vitro. Nature 331: 499–504
Krassikoff NE, Cowan JM, Parry DM, Francke U (1986) Chromatid repulsion associated with Roberts/SC phocomelia syndrome is reduced in malignant cells and not expressed in interspecies somatic-cell hybrids. Am J Hum Genet 39: 618–630
Lenz WD, Marquardt E, Weicker H (1974) Pseudothalidomide syndrome. Birth Defects 10: 97–107
Magnuson T, Epstein CJ (1984) Oligosyndactyly: A lethal mutation in the mouse that results in mitotic arrest very early in development. Cell 38: 823–833
Mason JM (1976) Orientation Disruptor (ord): a recombination-defective and disjunction-defective meiotic mutant in Drosophila melanogaster. Genetics 84: 545–572
Mitchison T, Evanz L, Schulze E, Kirschner M (1986) Sites of microtubule assembly and disassembly in the mitotic spindle. Cell 45: 515–527
Morris NR (1980) Chromosome structure and the molecular biology of mitosis in eukaryotic micro-organisms. In Gooday GW, Lloyd D, Trinci APJ (eds) Eukaryotic microbial cell. Cambridge University Press, Cambridge, pp 41–75
Parry DM, Mulvihill JJ, Tsai S, Kaiser-Kupfer MI, Cowan JM (1986) SC Phocomelia syndrome, premature centromere separation, and congenital cranial nerve paralysis in two sisters, one with malignant melanoma. Am J Med Genet 24: 653–672
Petrinelli P, Antonelli A, Marcucci L, Dallapiccola B (1984) Premature centromere splitting in a presumptive mild form of Roberts syndrome. Hum Genet 66: 96–99
Pfarr CM, Coue M, Grissom PM, Hays TS, Porter ME, McIntosh JR (1980) Cytoplasmic dynein is localized to the kinetochores during mitosis. Nature 345: 263–265
Pfeiffer RA, Zwerner H (1982) The Roberts syndrome. Report of a case without anomaly of the centromeric region. Monatsschr Kinderheilkd 130: 296–298
Pinkel D, Straume T, Gray JW (1988) Cytogenetic analysis using quantitative, high-sensitivity, fluorescence hybridization. Proc Natl Acad Sci USA 83: 2934–2938
Roberts JB (1919) A child with double cleft of lip and palate, protrusion of the intermaxillary portion of the upper jaw and imperfect development of the bones of the four extremities. Ann Surg 70: 252–254
Romke C, Froster-Iskenius U, Heyne K, Hohn W, Hof M, Grzejszczyk G, Rauskolb R, Rehder H, Schwinger E (1987) Roberts syndrome and SC phocomelia: A single genetic entity. Clin Genet 31: 170–177
Schinzel A (1984) Trisomy 7. In: Catalogue of unbalanced chromosome aberrations in man. Walter de Gruyter, Berlin New York, p 294
Shah SB, Deshpande VS, Kalyani R, Patel DN (1984) Roberts' syndrome. Indian Pediatr 21: 500–502
Stanley WS, Pai GS, Horger EO, Yongshan Y, McNeal KS (1988) Incidental detection of premature centromere separation in amniocytes associated with a mild form of Roberts syndrome. Prenat Diagn 8: 565–569
Steel CM, Shade M, Woodward MA (1980) Chromosome aberrations acquired in vitro by human B-cell lines I. Gains and losses of material. J Natl Cancer Inst 64: 95–98
Steuer ER, Wordeman L, Schoer TA, Sheetz MP (1990) Localization of cytoplasmic dynein to mitotic spindles and kinetochores. Nature 345: 266–268
Stoll C, Levy JM, Beshara D (1979) Roberts' syndrome and clonidine. J Med Genet 16: 486–488
Sumner AT (1972) A simple technique for demonstrating heterochromatin. Exp Cell Res 75: 304–306
Tomkins D, Hunter A, Roberts M (1979) Cytogenetic findings in Roberts'-SC phocomelia syndrome(s). Am J Med Genet 4: 17–26
Tomkins DJ, Sisken JE (1984) Abnormalities in the cell-division cycle in Roberts syndrome fibroblasts: a cellular basis for the phenotypic characteristics? Am J Hum Genet 36: 1332–1340
Waldenmaier C, Aldenhoff P, Klemm T (1978) Roberts' syndrome. Hum Genet 40: 345–349
Waye JS, England SB, Willard HF (1987) Genomic organization of alpha satellite DNA on human chromosome 7: evidence for two distinct alphoid domains on a single chromosome. Mol Cell Biol 7: 349–356
Wertelecki W, Logsdon P, Dev VG (1983) Multiple premature centromere separation in a patient without Roberts syndrome. Am J Hum Genet 35: 160 A
Wertelecki W, Dev VG, Superneau DW (1985) Abnormal centromere-chromatid apposition (ACCA) and Peters' anomaly. Ophthalmic Paediatr Genet 6: 7–15
Wissinger W, Wang RJ (1978) Studies on cell division in mammalian cells IV. A temperature-sensitive cell line defective in postmetaphase chromosome movement. Exp Cell Res 112: 89–94
Yunis JJ, Chandler ME (1977) High-resolution chromosome analysis in clinical medicine. I: Stefanini M, Hossaini A (eds) Progress in clinical pathology, vol 7. Grune & Stratton, New York, pp 267–288
Yunis JJ, Sawyer JR, Ball DW (1978) The characterization of high resolution G-banded chromosomes in man. Chromosoma 67: 293–307
Author information
Authors and Affiliations
Additional information
by T.C. Hsu
Rights and permissions
About this article
Cite this article
Jabs, E.W., Tuck-Muller, C.M., Cusano, R. et al. Studies of mitotic and centromeric abnormalities in Roberts syndrome: Implications for a defect in the mitotic mechanism. Chromosoma 100, 251–261 (1991). https://doi.org/10.1007/BF00344159
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00344159