The immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome is a rare autosomal recessive disease. Usually, it is caused by mutations in the DNA methyltransferase 3B gene, which result in decreased methylation of satellite DNA in the juxtacentromeric heterochromatin at 1qh, 16qh, and 9qh. Satellite II-rich 1qh and 16qh display high frequencies of abnormalities in mitogen-stimulated ICF lymphocytes without these cells being prone to aneuploidy. Here we show that in lymphoblastoid cell lines from four ICF patients, there was increased colocalization of the hypomethylated 1qh and 16qh sequences in interphase, abnormal looping of pericentromeric DNA sequences at metaphase, formation of bridges at anaphase, chromosome 1 and 16 fragmentation at the telophase-interphase transition, and, in apoptotic cells, micronuclei with overrepresentation of chromosome 1 and 16 material. Another source of anaphase bridging in the ICF cells was random telomeric associations between chromosomes. Our results elucidate the mechanism of formation of ICF chromosome anomalies and suggest that 1qh-16qh associations in interphase can lead to disturbances of mitotic segregation, resulting in micronucleus formation and sometimes apoptosis. This can help explain why specific types of 1qh and 16qh rearrangements are not present at high frequencies in ICF lymphoid cells despite diverse 1qh and 16qh aberrations continuously being generated.
We have found that lethal toxin from Clostridium sordellii, which specifically inactivates the low molecular weight G proteins Ras, Rap, and Rac, inhibits the activation of p38 mitogen-activated protein kinase (
Most osteosarcomas are highly aggressive malignancies characterized by a complex pattern of chromosome abnormalities. However, a subgroup of low-grade, parosteal tumors exhibits a relatively simple aberration pattern dominated by ring chromosomes carrying amplified material from chromosome 12. To assess whether sequences from this chromosome were differentially amplified in low- and high-grade osteosarcomas, copy numbers of the CCND2, ETV6, KRAS2, and D12S85 regions in 12p and the MDM2 region in 12q were evaluated by interphase or metaphase fluorescence in situ hybridization (FISH) in 24 osteosarcomas. Amplification of MDM2 was detected in all five low-grade and four high-grade osteosarcomas, all of which showed ring chromosomes. An overrepresentation of 12p sequences was found in 1/5 low-grade and in 9/19 high-grade tumors. Multicolor single-copy FISH analysis of metaphase cells from six high-grade tumors showed that extra 12p material either occurred together with MDM2 in ring chromosomes or was scattered over the genome as a result of complex structural rearrangements. Most tumors (8/10) not containing amplification of the assessed chromosome 12 loci exhibited a nondiploid pattern at evaluation with probes for centromeric alpha satellite sequences. These findings indicate that gain of sequences from the short arm of chromosome 12 could be a possible genetic pathway in the development of aggressive osteosarcoma.
We examined, cytogenetically and by in situ hybridization (ISH) techniques, the synovia, osteophytes, and articular cartilage from 32 patients with pronounced osteoarthritis (OA), a prevalent form of arthropathy characterized by progressive reduction of articular cartilage, and synovial samples from 17 control patients. In short-term cultures, clonal chromosome aberrations, in particular the gain of chromosomes 7 (+7) and 5 (+5), were found to be strongly associated with OA. These aberrations were found in almost 90% of the cultures from synovia and osteophytes, whereas only 1/11 synovial samples from joints unequivocally unaffected by OA had cells with +5 or +7. The in vivo nature of trisomy 7 was demonstrated by ISH on uncultured cells, and serial passaging showed that cells with +7 had a proliferative advantage in vitro. Thus, the combined data indicate that cells with somatic mutations appear early and may be influential in the disease process leading to OA.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.