Premature Centromere Separation Research Articles

Clinical heterogeneity of skeletal dysplasia in Roberts syndrome: a review.

Roberts syndrome is a rare autosomal recessive disorder with highly variable clinical features. The most notable manifestations include pre- and postnatal growth retardation, craniofacial anomalies and improper development of all four extremities. We reviewed 50 cases whose clinical evaluation has been vigorously pursued. A relationship of deformities exists between humerus versus femur, and radius and ulna versus tibia and fibula. Only six cases had clubfoot. The number of fingers and toes was variable. The sex ratio was 1:1. Most individuals died in early infancy, although the longest follow-up survival was 13 years in one case. Premature centromere separation, centromere splitting and puffing were common chromosomal abnormalities. An annotated bibliography on notable cases is also provided which should serve as an aid for clinicians who wish to further understand the genetic and clinical heterogeneity noted in their cases.

The influence of postovulatory ageing on the retardation of mouse oocyte maturation and chromosome segregation induced by vinblastine.

Certain compounds can induce ovulated metaphase I (MI) oocytes. To study if these MI oocytes can overcome this blockage, ICR mice were given human chorionic gonadotrophin and 0.6 mg/kg vinblastine sulfate (VBS). Their ovulated oocytes were collected at 17, 19, 21, 23 and 25 h later. The results showed that the frequencies of MI oocytes decreased, the proportions of diploid metaphase II (MII) oocytes increased and the frequencies of hyperploid MII oocytes did not significantly differ (P > 0.05) among the five harvest or postovulatory times. We also found that the proportions of MII oocytes exhibiting premature anaphase II and premature centromere separation increased with postovulatory ageing, and that these frequencies were consistently higher in controls than in the VBS groups. These findings indicate that some of the oocytes blocked in MI can overcome this inhibition and produce primarily diploid MII oocytes. The ultimate fate of ovulated MI and diploid oocytes on aneuploid production hinges upon the formation of a functioning meiotic spindle, which is affected by both dosage and the specific chemical.

The Baller-Gerold syndrome: phenotypic and cytogenetic overlap with Roberts syndrome.

A case is reported where the major clinical features of craniostenosis and radial aplasia led to an initial diagnosis of Baller-Gerold syndrome. Mild fibular hypoplasia on skeletal survey led to review of the diagnosis and the similarity of the facial phenotype to that of Roberts syndrome was noted. Chromosome analysis showed the premature centromere separation characteristic of this condition. This case raises the question as to whether the Baller-Gerold syndrome can be considered as a distinct entity. It is suggested that cases diagnosed as having Baller-Gerold syndrome should have cytogenetic analysis and that known Roberts syndrome survivors are reviewed for signs of craniostenosis.

Centromere structure and function in neoplasia.

The mammalian centromere plays an essential role in maintenance of diploidy in the cell. It is therefore imperative that we understand the structure and function of the mammalian centromere in order to plan strategy to control the incidence of aneuploidy and resultant malformations of the nonneoplastic as well as neoplastic tissues. Even though considerable information is available about the structure and some functional aspects of centromeres of lower eukaryotes such as yeast, the structure of the mammalian centromere is still a matter of conjecture limited to an understanding of the base composition of the alphoid sequences putatively located in the centromeric DNA of higher apes. We do, however, have a better understanding of the structure and role of the kinetochore. In all eukaryotes analyzed so far, the centromeres in a given genome separate in a sequential manner dependent upon the time of replication of pericentric and centromeric DNA. Some chromosomes, generally found in neoplastic cells, that carry more than one centromere show premature separation of the accessory centromeres. These centromeres and the associated pericentric regions replicate their DNA in an earlier part of the S phase than those that show kinetochore activity; both, however, carry DNA of the same composition. The active centromeres in these chromosomes show kinetochore protein binding as detected by antikinetochore antibody; the inactive centromeres are usually devoid of these proteins. The double minutes in neoplastic cells also lack kinetochore proteins, perhaps due to a lack of any centromere. Some dicentric and multicentric chromosomes in cancer cells and transformed cell lines do not display premature centromere separation. In these chromosomes, all centromeric sites show kinetochore proteins and all centromeric regions replicate their DNA simultaneously. These chromosomes also exhibited meiotic-like behavior of some centromeres and show postanaphase separation of some centromeres, resulting in bridges. These bridges, upon breakage and rejoining of sister chromatids, generate new multicentric chromosomes. The resulting chromosomes also exhibit formation of compound kinetochores. Some of these phenomena are novel descriptions of the centromere behavior in cancer cells. This review also discusses the role of aberrant centromere separation in human biology, providing correlates between errors of centromere separation and neoplasia.

Sequence of centromere separation: characterization of multicentric chromosomes in a rat cell line.

The B1 cell line of rat cerebral endothelium origin exhibits several dicentric and multicentric chromosomes. These chromosomes, unlike multicentrics in mouse (Vig and Zinkowski 1986) do not show premature centromere separation. All centromeres deposit kinetochore proteins and appear to be functional. Even the centromeres which fail to migrate to the poles during anaphase and make side arm bridges bind to spindle microtubules. Some multicentric chromosomes show kinetochores spaced apart with intervening stretches of euchromatin while others are located adjacent to each other thus exhibiting tandem repeats and forming a "compound" kinetochore (Brinkeley et al. 1984). Also, unlike mouse multicentric chromosomes in which different pericentric regions and the centromeres replicate at different times, the rat chromosomes appear to replicate all pericentric and centric regions in a given multicentric simultaneously. The present studies indicate that centromeres in rat and mouse replicate during the last part of the S-phase and in continuation with the pericentric heterochromatin.

Sequence of centromere separation: Kinetochore formation and DNA replication in dicentric chromosomes showing premature centromere separation in rat cerebral cells

A subpopulation of rat cerebral endothelial cells, designated B1, exhibits an array of multicentric chromosomes. Because of the formation of bridges at anaphase, this cell population produced new types of multicentrics at every cell division [7]. These chromosomes showed kinetochore proteins at every centromeric site and all centromeric regions replicated their DNA at the end of the S phase, more or less simultaneously [1]. A new subpopulation of cells, designated B2, obtained from the original sample frozen at Wayne State University displayed several dicentrics. In contrast to B1 these chromosomes exhibit premature centromere separation as reported for mouse and human cell lines [8]. These B2 dicentrics show only one site of kinetochore protein deposition. The timing of DNA replication around the centric region of prematurely separating centromere is also changed similar to the earlier reported premature DNA synthesis for mouse dicentrics. These observations suggest a universality of relationship between premature centromere separation, a lack of kinetochore formation, and early replication of the centric/pericentric DNA associated with these centromeres. The cause of sudden change from activity to inactivity of these chromosomes, though interesting, is not clear.

Premature separation of centromeres in marrow chromosomes from an untreated patient with acute myelogenous leukemia

Cytogenetic studies in an untreated patient with acute myelogenous leukemia revealed that greater than 60% of his marrow metaphases had pronounced anomalies in the centromere region. In the least affected chromosomes, the centromere appeared as a nonstaining hole, whereas in the most affected chromosomes, it appeared that the centromere segment had prematurely migrated at right angles to the telomeric portions. The population of mitoses exhibiting premature separation of the centromeres was reduced to virtually none during periods of drug induced remission. Our findings suggest that cytogenetic changes in malignant myeloid cells may be characterized by defects in centromere separation, as well as by alterations in karyotype.