We have examined unfertilised oocytes and their first polar bodies (PBs) to determine the way in which the frequency of whole chromosome imbalance compares with that involving single chromatids and whether the precocious separation of chromatids prior to anaphase I affects all pairs of chromosomes. We have applied the technique of fluorescent in situ hybridisation in a three-stage method by using locus-specific probes for chromosomes 13 and 21 and alpha-satellite probes for chromosomes 1, 9, 16, 18 and X to determine the chromosome status of oocytes and their PBs. We obtained analysable results from 127 oocytes and 57 PBs from 72 patients of average age 33 years. Six oocytes and three PBs had extra signals but, of these, three were derived from a single patient, aged 26. Anomalies were seen in chromosomes 13, 16, 18, X and, notably, 21 but none were observed in chromosomes 1 and 9. Half of the anomalies involved additional chromatids rather than whole chromosomes. Since particular chromatids were found to be prematurely separated in the metaphase II oocyte, this may provide further evidence for an additional mechanism of maternal aneuploidy that operates at anaphase II. Detailed analyses of both oocytes and PBs have elucidated possible mechanisms leading to aneuploid gametes in this group of patients with fertility problems.
Human UDP-glucuronosyltransferases (UDPGTs) are a family of enzymes which detoxify many hundreds of compounds by their conjugation to glucuronic acid, rendering them both harmless and more water soluble, hence, excretable. The level of expression of each UDPGT isoform in the body is the result of interplay between temporal, tissue-specific and environmental regulators. This complexity contributes to the difficulty in predicting the metabolic fate of compounds. Genetic defects and polymorphisms affecting individual isoform activities have deleterious and potentially lethal effects, as exemplified by the severe hyperbilirubinaemia observed in Crigler-Najjar Syndrome. Such severe genetic defects in bilirubin glucuronidation are obvious candidates for antenatal screening and gene therapy.
We have examined unfertilised oocytes and their first polar bodies (PBs) to determine the way in which the frequency of whole chromosome imbalance compares with that involving single chromatids and whether the precocious separation of chromatids prior to anaphase I affects all pairs of chromosomes. We have applied the technique of fluorescent in situ hybridisation in a three-stage method by using locus-specific probes for chromosomes 13 and 21 and alpha-satellite probes for chromosomes 1, 9, 16, 18 and X to determine the chromosome status of oocytes and their PBs. We obtained analysable results from 127 oocytes and 57 PBs from 72 patients of average age 33 years. Six oocytes and three PBs had extra signals but, of these, three were derived from a single patient, aged 26. Anomalies were seen in chromosomes 13, 16, 18, X and, notably, 21 but none were observed in chromosomes 1 and 9. Half of the anomalies involved additional chromatids rather than whole chromosomes. Since particular chromatids were found to be prematurely separated in the metaphase II oocyte, this may provide further evidence for an additional mechanism of maternal aneuploidy that operates at anaphase II. Detailed analyses of both oocytes and PBs have elucidated possible mechanisms leading to aneuploid gametes in this group of patients with fertility problems.
Mitochondria from a patient heteroplasmic at nucleo-tide position 8993 of mitochondrial DNA (mtDNA) were introduced into two human tumour cell lines lacking mtDNA. The donor mitochondria contained between 85 and 95% 8993G:C mtDNA. All detectable mtDNA in the mitochondrially transformed cells contained the pathological 8993G:C mutation 3 months after transformation. These results suggest that 8993G:C mtDNA had a selective advantage over 8993T:A mtDNA in both lung carcinoma and osteo-sarcoma cell backgrounds. In contrast, two other presumed pathological mtDNA variants were lost in favour of 'wild-type' mtDNA molecules in the same lung carcinoma cell background. Taken together, these findings suggest that the transmission bias of mtDNA variants is dependent upon a combination of nuclear background and mtDNA genotype. A second phenomenon observed was a marked decrease in the growth rate of many putative transformed cell lines after 6 weeks of culturing in selective medium, and in these cell lines mtDNA was not readily detectable by Southern blotting. Restriction endonuclease analysis and sequencing of amplified mtDNA demonstrated that the slow growing cells contained little or no mtDNA. It is concluded that these cells represented transient mitochondrial transformants.
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