Albright hereditary osteodystrophy (AHO) is a condition with characteristic physical findings (short stature, obesity, round face, brachydactyly) but variable biochemical changes (pseudohypoparathyroidism, pseudopseudohypoparathyroidism). Most patients with AHO have decreased activity of the guanine nucleotide-binding protein (GS protein) that stimulates adenylyl cyclase. The gene encoding the alpha subunit of the GS protein (GNAS1) has been mapped to the long arm of chromosome 20. We describe 4 unrelated individuals with apparent AHO, associated with small terminal deletions of chromosome 2. All 4 patients had normal serum calcium levels consistent with pseudopseudohypoparathyroidism. Del(2) (q37) is the first consistent karyotypic abnormality that has been documented in AHO [Phelan et al., 1993: Am J Hum Genet 53:484]. The finding of the same small terminal deletion in 4 unrelated individuals with a similar phenotype suggests that a gene locus in the 2q37 region is important in the pathogenesis of Albright syndrome. The association of Albright syndrome and the GNAS1 locus on chromosome 20 is well documented. The observation of a second potential disease locus on chromosome 2 may help explain the heterogeneity observed in this disorder.
We have collected and analyzed clinical information from 11 patients with chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients' deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf-Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and chromosome deletion studies.
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome demonstrating heterogeneous molecular alterations of two imprinted domains on chromosome 11p15. The most common molecular alterations include loss of methylation at the proximal imprinting center, IC2, paternal uniparental disomy (UPD) of chromosome 11p15 and hypermethylation at the distal imprinting center, IC1. An increased incidence of female monozygotic twins discordant for BWS has been reported. The molecular basis for eleven such female twin pairs has been demonstrated to be a loss of methylation at IC2, whereas only one male monozygotic twin pair has been reported with this molecular defect. We report here two new pairs of male monozygotic twins. One pair is discordant for BWS; the affected twin exhibits paternal UPD for chromosome 11p15 whereas the unaffected twin does not. The second male twin pair is concordant for BWS and both twins of the pair demonstrate hypermethylation at IC1. Thus, this report expands the known molecular etiologies for BWS twins. Interestingly, these findings demonstrate a new epigenotype-phenotype correlation in BWS twins. That is, while female monozygotic twins with BWS are likely to show loss of imprinting at IC2, male monozygotic twins with BWS reflect the molecular heterogeneity seen in BWS singletons. These data underscore the need for molecular testing in BWS twins, especially in view of the known differences among 11p15 epigenotypes with respect to tumor risk.
Diploid human fibroblast strains were treated for 10 min with inhibitors of type I and type II DNA topoisomerases, and after removal of the inhibitors, the rate of initiation of DNA synthesis at replicon origins was determined. By alkaline elution chromatography, 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsa- DNA topoisomerases are a class of nuclear enzymes which are capable of forming covalent complexes with DNA. Formation of these complexes involves scission of the phosphodiester backbone of DNA, with covalent linkage of the topoisomerase to one end of the cutting site (6, 13, 40). The other cut end apparently remains associated with the topoisomerase. These complexes of topoisomerase associated with cut or cleaved DNA are known as cleavable complexes. For type I topoisomerases from mammalian cells, a single DNA break is produced in the complex, and free rotation of the cut strand about the intact strand allows relaxation of supercoiled molecules. Type II topoisomerases produce closely opposed cuts in the two strands of duplex DNA, allowing passage of strands through the DNA duplex.The formation of topoisomerase-DNA complexes which allow relaxation of supercoiled DNA or passage of double strands of DNA may facilitate transcription of RNA and replication of DNA (3, 5, 9). Both type I and type II topoisomerases have been shown to play roles in replication of the simian virus 40 (SV40) circular replicon in a cell-free system (37, 42). Topoisomerase I was found to contribute to chain elongation, presumably by relieving supercoiling tension in front of advancing replication forks. This function could be replaced by topoisomerase II. Topoisomerase II was also required for the final stages of separation of the topologically intertwined sister duplexes. This result was consistent with demonstrations that temperature-sensitive topoisomerase II yeast mutants were arrested in G2 when incubated at the restrictive temperature (7). Recent results also implicate topoisomerases as endogenous suppressors of homologous recombination (41). The vital nature of these enzyme activities is exemplified by the demonstration that they are the targets for a variety of cytotoxic drugs used clinically to treat certain cancers (34,39). Many of these drugs stabilize the topoisomerase-DNA cleavable complex, and the resulting DNA strand breaks can be discerned with a strong protein denaturant. Topoisomerase inhibitors produce dramatic cytogenetic damage, including sister chromatid exchange and chromosome aberrations (17). Thus, the mechanism of drug action is of interest for the rational design of drug therapy regimens.To date, there have been few studies of the mechanisms of inhibition of DNA replication by drugs which interfere with topoisomerase activity. Flow cytometric analysis had revealed a delayed progression of human leukemic cells through S phase during incubation with etoposide [4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-p-D-glucopyranoside)], an inhibitor of type II topoisomerase (16). Inhibition of DNA synthesis wa...
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