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PubMed1994

Mosaic expression of an Hprt transgene integrated in a region of Y heterochromatin.

The sensitivity of small transgenes to position effects on their expression suggests that they could serve as indicators of the chromatin properties at their integration site. In particular, they might be expected to provide information on the functional properties of mammalian heterochromatin. We have produced a transgenic line that carries a mouse Hprt minigene on the Y chromosome. In situ hybridization localized the transgene to the heterochromatic portion of the Y. Analysis of transgene expression by isoelectric focusing indicated that the transgene is expressed in a mosaic pattern, and expressing cells have different levels of transgene activity. These findings can be explained as a position effect variegation induced by Y heterochromatin. However, two other transgenes, located at autosomal sites, also showed mosaic activity. If the mosaic transgene expression is attributed to the influence of the chromatin at the insertion site, the Y heterochromatin would appear less potent than some autosomal regions at inducing variegation. An alternative explanation consistent with our results is that the mosaic expression is a semi-autonomous characteristic of these transgene loci. Transgene-expressing and non-expressing cells differed in their ability to grow and be cloned in vitro, indicating that cellular differentiation affected the chromatin structure of the transgene locus on the Y. Karyotype analysis of male mice with the Y-linked transgene and from control male mice carrying the human HPRT transgene, or the mouse Pgk-1 gene at autosomal sites, indicated that the transgene-carrying Y is prone to non-disjunction, generating cells with two (or more) or no Y chromosomes in equal proportion. Further studies will determine if the propensity of this Y chromosome to mitotic errors is also observed in vivo.

Animals↗

PubMed2006

Comparative morphology of the bursal nozzles in acoels (Acoela, Acoelomorpha).

Systematics of the Acoela is particularly difficult because of the paucity of readily discernible morphological features. In other soft-bodied worms, sclerotized structures, such as copulatory stylets, provide important characters that can be seen in whole mounts, but acoels generally lack such features. Among the few sclerotized structures in acoels are bursal nozzles-tubiform outlets on the seminal bursae that are believed to be conduits (spermatic ducts) through which allosperm are transported to the oocytes. Early classifications of the Acoela used features of the female reproductive system, including bursal nozzles, for distinguishing major groups, but the current system essentially ignores them as too plastic to provide higher-level distinctions. We used confocal and electron microscopy to further characterize bursal nozzles in five acoel species, and found all composed of actin-reinforced extensions of stacked, flat mesenchymal cells. In Notocelis gullmarensis, Aphanostoma bruscai, and Daku woorimensis, the nozzle is a stiffened region of the same cells forming the wall of the bursa. By contrast, in Wulguru cuspidata cells forming the nozzle are distinct from those of the bursa. The so-called bursal cap of A. bruscai and D. woorimensis has small sclerotized disjunct units within it, also composed of stacked, flat, actin-reinforced cells. The nozzle of W. cuspidata, prominent like that of other convolutid acoels, is relatively complex, its actin-reinforced cells sandwiched with secretory cells and its base bearing a "sorting apparatus" of egg-shaped cells that send narrow processes inside the spermatic duct. Cases of sperm inside the nozzle corroborate its assumed role in reproduction. Whereas most nozzles sit at the end of the bursa facing the ovary, in species of Pseudmecynostomum and purportedly in a few other acoels, they sit between the female pore and the bursa, constituting what we call a vaginal nozzle. All bursal nozzles of acoels show a common ground pattern indicating common ancestry, but certain features discerned through electron and confocal microscopy show promise of providing synapomorphies for grouping some species.

Animal Structures↗

PubMed1977

A surgical technique for resecting malignancies invading the facial nerve and petrous pyramid.

Certain head and neck malignancies tend to invade branches of the cranial nerves and progress centripetally. The maxillary and mandibular divisions of the V (trigeminal) nerve are the most commonly invaded, but the VII (facial) nerve may harbor extensions of primary parotid malignancies and/or skin cancers originating in or near the ear. Paresis of the VII nerve signifies a serious but not entirely hopeless situation if countered with an appropriate surgical procedure. The optimal treatment of malignancies invading cranial nerves is surgical excision, which may necessitate removal of substantial portions of the cranium. Surgical pursuit of a malignancy in the facial nerve leads to a direct confrontation with the petrous pyramid of the temporal bone. Resection of the petrous pyramide is surgically feasible, but, if performed en bloc, extracts a high morbidity and mortality. An alternate technique in which the soft tissue and bones are removed disjunct is advocated. In this technique, the soft tissues are excised flush with the surface of the temporal bone. After making perforator and burr openings in the squamous temporal bone, a subtotal temporal craniectomy is completed with rongeurs. A prerequisite for success with this technique is the rotation of a large scalp flap and other local flaps to cover the exposed meninges and carotid arteries. A resume of four cases using this technique is presented. The age of the patients, the type, stage, and duration of the malignancies, and other factors which might influence the end stage results are given.

Aged↗

PubMed2005

Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra.

Genomic convergence is a multistep approach that combines gene expression with genomic linkage to identify and prioritize susceptibility genes for complex disease. As a first step, we previously performed linkage analysis on 174 multiplex Parkinson's disease (PD) families, identifying five peaks for PD risk and two for genes affecting age at onset (AAO) in PD [Hauser et al., Hum Mol Genet 2003;12:671-677]. We report here the next step: serial analysis of gene expression [SAGE; Scott et al., JAMA 2001;286:2239-2242] to analyze substantia nigra tissue from three PD patients and two age-matched controls. We find 933 differentially expressed genes (P<0.05) between PD and controls, but of these, only 50 genes represented by unique SAGE tags map within our previously described PD linkage regions. Furthermore, genes encoded by mitochondrial DNA are expressed 1.5-fold higher in PD patients versus controls, without an increase in the corresponding nuclear-encoded mitochondrial components, suggesting an increase in mtDNA genomes in PD or a disjunction with nuclear expression. The next step in the genomic convergence process will be to screen these 50 high-quality candidate genes for association with PD risk susceptibility and genetic effects on AAO.

Aged↗

PubMed2005

A comparison of maternal age, sex ratio and associated major anomalies among fetal trisomy 18 cases with different cell division of error.

OBJECTIVES: To compare the maternal age, sex ratio, and associated major anomalies among fetal trisomy 18 cases with different cell division of error. METHODS: Thirty-one consecutive cases of fetal trisomy 18 detected perinatally during a period of 6 years were studied. Among these, 18 were 47,XY,+18, and 13 were 47,XX,+18. The average gestational age at diagnosis was 19.7 +/- 4.6 weeks, and the maternal age at diagnosis was 34.5 +/- 5.8 years. DNA polymorphism analysis was applied to determine the parental origin, stage of non-disjunctional error and recombination. RESULTS: Twenty-eight cases were of maternal origin. Among these, 20 had major anomalies, 17 had meiosis II (MII) errors, 10 had meiosis I (MI) errors, and one had a postzygotic mitotic (PZM) or non-crossover MII error. Three cases were of paternal origin. Among these, two had major anomalies, two had MI errors, and one had a PZM or non-crossover MII error. For the 17 cases with maternal MII errors, the average maternal age was 34.5 +/- 6.6 years. Of these cases, 12 had major anomalies, 13 were male, and 4 were female, giving a male:female sex ratio of 3.25:1. For the 10 cases with maternal MI errors, the average maternal age was 34.8 +/- 5.7 years. Of these cases, seven had major anomalies, three were male, and seven were female, giving a male:female sex ratio of 0.429:1. CONCLUSION: In trisomy 18, there is a male preponderance in the fetuses caused by maternal MII errors and a female preponderance in the fetuses caused by maternal MI errors. No significant difference was noted in maternal age or in associated major anomalies between the two groups of maternal MII errors and maternal MI errors. No significant difference was noted in associated major anomalies between the maternal and paternal cases.

Adult↗

PubMed2006

Complete discrepancy between abnormal fetal karyotypes predicted by QF-PCR rapid testing and karyotyped cultured cells in a first-trimester CVS.

A chorion villus sample (CVS) biopsied at 11 weeks' gestation for raised nuchal translucency, revealed monosomy X (presumptive 45,X karyotype) by QF-PCR for rapid aneuploidy testing for chromosomes 13, 18, 21, X and Y. Long-term culture gave the karyotype: 47,XY,+ 21[66]/49,XYY,+ 21,+ 21 [22]. This discrepancy prompted redigestion of the combined residual villus fragments from the original QF-PCR assay. The repeat QF-PCR assay identified the presence of trisomy 21 and a Y chromosome consistent with a 47,XY,+ 21 karyotype. A double non-disjunction event early in embryogenesis in a 47,XY,+ 21 conceptus with subsequent cell lineage compartmentalisation of the three observed cell lines (45,X; 47,XY,+ 21 and 49,XYY,+ 21,+ 21) would account for these results. This is the first reported case to describe complete discrepancy at diagnosis between abnormal karyotypes detected by QF-PCR rapid aneuploidy testing and a cultured karyotype in the same CVS.

Adult↗

PubMedDate not supplied

Further examples of trisomy-20 mosaicism in amniotic cell cultures.

Amniotic fluid cultures from two patients showed trisomy-20 mosaicism. No trisomy-20 cells were found in a normal full term infant and in multiple tissue biopsies and fetal blood from a fetus after a termination of pregnancy. No definitive advice is yet possible for parents where trisomy-20 amniotic cell mosaicism is detected. Fetoscopy and fetal blood sampling are of no value and termination of pregnancy is not indicated by empirical evidence. Preferential trophoblastic non-disjunction (Kalousek and Dill, 1983) is discussed as a possible partial explanation for the variable occurrence and distribution of this type of mosaicism.

Adult↗

PubMed1988

An embryogenic model to explain cytogenetic inconsistencies observed in chorionic villus versus fetal tissue.

While the fetus and placenta have a common ancestry, chorionic villus tissue does not always reflect fetal genotype. Data are presented from 15 CVS subjects in whom cytogenetic inconsistencies were observed when comparing (1) cultured chorionic villi, (2) direct chromosome preparations of intact villi, and (3) cultured fetal tissue. Embryogenic models are presented to explain these discrepancies. Mosaicism confined to direct chromosome preparations was the most commonly observed inconsistency. This can be explained by postzygotic non-disjunction limited to cytotrophoblast. In all but one instance, the abnormal cell line was limited to the placenta, with the normal cell line reflecting fetal genotype. Analysis of direct chromosome preparations from multiple individually processed villus fragments may be helpful in recognizing mosaicism confined to the placenta. While both direct chromosome preparations and villus cultures can be misleading, the latter are more likely to reflect fetal genetic status since they are derived from the extraembryonic mesoderm.

Chorionic Villi↗

PubMed1990

Fetal blood sampling demonstrating chimerism in monozygotic twins discordant for sex and tissue karyotype (46,XY and 45,X)

Fetal blood sampling has been used in the genetic work-up of twin gestations for rapid karyotyping. We present a case of twins which on ultrasound evaluation revealed hydrops fetalis in one twin and a normal second twin. Fetal blood sampling revealed the presence of mosaicism for 46,XY/45,X in both twins. HLA antigen testing showed the twins to be identical. The patient elected pregnancy termination. Blood chromosomal analysis after delivery revealed both twins to have 46,XY/45,X mosaicism, but the twin with signs of hydrops fetalis had tissue chromosomes of 45,X and the normal twin had tissue chromosomes of 46,XY. Amniotic fluid chromosomal analysis revealed 46,XY in twin A and 45,X in twin B. This represents a case of identical (monozygotic) twins with sex discordance. In this case, there was the probable occurrence of post-zygotic chromosomal non-disjunction leading to the discordancy of the sex in this set of twins. With the presence of vascular communication in monozygotic twins, there is the possibility of exchange of blood in monozygotic twins and the result of blood chimerism in twins.

Adult↗

PubMed1990

Prenatal diagnosis of a double bisatellited marker with an unusual copy number ratio.

Prenatal diagnosis, by amniocentesis, revealed mosaicism with respect to a bisatellited, apparently dicentric, DA/DAPI positive, de novo marker. The following cell lines were observed in decreasing order of frequency: 46,XX greater than 48,XX,+mar,+mar much greater than 47,XX,+mar. The pregnancy was terminated and post-mortem examination revealed an apparently normal fetus. Cytogenetic studies of fetal and placental tissues revealed approximately the same level of mosaicism together with the unusual copy number ratio seen in the amniotic fluid cultures. Non-disjunction at the first post-zygotic mitotic division giving rise to a mosaic: 46,XX/48,XX,+mar,+mar followed by subsequent mitotic instability of the marker could account for the unusual copy number ratio.

Adult↗

PubMed1993

On the parental origin of the X's in a prenatally diagnosed 49,XXXXX syndrome.

A 49,XXXXX fetus was detected in amniotic fluid cell cultures from a 39-year-old mother. On ultrasonography, growth retardation and bilateral radioulnar synostosis were found. Additional clinical manifestations were mild facial anomalies and hypoplastic ovaries depleted of oocytes. Molecular analysis showed that this aneuploidy arose by successive maternal non-disjunction.

Adult↗

PubMed1995

46,XY,dup(10q) in direct CVS preparation and mosaic 48,XXXY,dup(10q) in CVS long-term culture and fetal tissue.

Chorionic villus sampling (CVS) was performed on a 40-year-old woman at 9 1/2 menstrual weeks because of advanced maternal age. The direct preparation showed 46,XY,dup(10)(q11.2q23.2). CVS long-term culture and fetal tissue revealed a rare additional abnormality: 48,XXXY,dup(10)(q11.2q23.2). This abnormality represented the major cell line (> 85 per cent in 691 cells) in an (XY)/XXY/XXXY/(XXXXY) mosaic (all cell lines presumably bearing the dup(10q); the presence of XY and XXXXY cell lines is uncertain). To our knowledge, this is the first report of trisomy 10q11-q23 and of prenatally detected 48,XXXY in chorionic villi. The mosaic could have resulted from early post-zygotic non-disjunctions in a 46,XY,dup(10q) or 47,XXY,dup(10q) zygote. The results from DNA studies of four polymorphisms, mapped to Xp and Xq, support this theory. The literature on prenatally detected cases with sex chromosome tetrasomy and pentasomy and those with additional autosomal abnormalities is reviewed. The reported case underlines the problem of false-negative findings when only direct CVS preparations are karyotyped.

Adult↗

PubMed1995

Mosaicism for trisomy 12: four cases with varying outcomes.

Trisomy 12 observed in chorionic villus sampling (CVS) may reflect generalized mosaicism or indicate mosaicism confined to only the placenta. In this report, four cases of trisomy 12 observed in CVS or cultured placental biopsies with varying outcomes are presented. Seven dinucleotide repeat polymorphisms for chromosome 12 were used to determine the chromosome 12 origins in the fetus or child and to delineate the mechanism(s) that gave rise to the trisomy. In two cases (cases A and C), the mosaicism was confined to the placenta, resulting in normal liveborns. Although, in one case, the molecular results suggested an apparent duplication of one paternal chromosome 12 in the placenta, normal biparental inheritance was found in the diploid fetal cell line in both cases. In two other cases (cases B and D), trisomy 12 was observed in both extraembryonic and fetal tissues. In one of these pregnancies, a child was born by Caesarean section at 37 weeks because of intrauterine growth retardation and oligohydramnios, and resulted in neonatal death. Molecular markers and fluorescence in situ hybridization (FISH) revealed low-level trisomy 12 mosaicism in the spleen. In the fourth case, fetal abnormalities were detected on ultrasound and low-level trisomy 12 mosaicism was observed in amniotic fluid cells using conventional cytogenetics and FISH. Molecular markers revealed a maternal meiosis I non-disjunction of chromosome 12 in DNA from a cultured placental biopsy. Although predicting the outcomes of pregnancies involving confined placental mosaicism remains difficult, molecular techniques are valuable tools for distinguishing uniparental from biparental disomy and mechanisms of mosaicism.

Adult↗

PubMed2003

Three different origins for apparent triploid/diploid mosaics.

Four apparent triploid/diploid mosaic cases were studied. Three of the cases were detected at prenatal diagnosis and the other was of an intellectually handicapped, dysmorphic boy. Karyotypes were performed in multiple tissues if possible, and the inheritance of microsatellites was studied with DNA from fetal tissues and parental blood. Non-mosaic triploids have a different origin from these mosaics with simple digyny or diandry documented in many cases. Three different mechanisms of origin for these apparent mosaics were detected: (1) chimaerism with karyotypes from two separate zygotes developing into a single individual, (2) delayed digyny, by incorporation of a pronucleus from a second polar body into one embryonic blastomere, and (3) delayed dispermy, similarly, by incorporation of a second sperm pronucleus into one embryonic blastomere. In three of the four cases, there was segregation within the embryos of triploid and diploid cell lines into different tissues from which DNA could be isolated. In case 2 originating by digyny, the same sperm allele at each locus could be detected in both triploid and diploid tissues, which is supportive evidence for the involvement of a single sperm and for true mosaicism rather than chimaerism. Similarly, in case 4 originating by dispermy, the same single ovum allele at each locus could be detected in diploid and triploid tissues, confirming mosaicism. In the chimaeric case (case 3), the diploid line had the karyotype 47,XY,+16 while the triploid line was 69,XXY. This suggests a chimaera, since, in a true mosaic, the triploid line should also contain the additional chromosome 16. Supporting the interpretation of a chimaeric origin for this case, the DNA data showed that the triploidy was consistent with MII non-disjunction (i.e. involving a diploid ovum). In the mosaic cases (1, 2, 4), there was no evidence of the involvement of a diploid sperm or a diploid ova, and in triploid/diploid mosaicism, an origin from a diploid gamete is excluded, since all such conceptuses would be simple triploids. In one of these triploid/diploid mosaics detected at prenatal diagnosis by CVS, the triploid line seemed to be sequestered into the extra-fetal tissues (confined placental mosaicism). This fetus developed normally and a normal infant was born with no evidence of triploidy in newborn blood or cord blood at three months of age.

Female↗

PubMed2003

Sequential FISH analysis of oocytes and polar bodies reveals aneuploidy mechanisms.

OBJECTIVES: Constitutional aneuploidy occurs in at least 5% of recognised pregnancies, with apparent preferential involvement of the X chromosome and the smaller autosomes. Molecular cytogenetic investigations of cleavage-stage embryos have revealed anomalies affecting all sizes of chromosomes. The aim was to investigate the variety of anomalies arising during maternal meiosis I by analysis of unfertilised oocytes and polar bodies to gain insight into aneuploidy mechanisms. METHODS: Sequential FISH analysis was carried out with specific probes derived from eight chromosomes, representing all sizes. Only imbalance due to a gain of a whole chromosome or chromatid, represented by extra signals, was counted to avoid artefact. RESULTS: Data were obtained on 236 eggs from 124 patients of average age 32.5 years (range 22-44). Ten patients (average 32.6 years) had abnormal eggs. The abnormality rate for oocytes and for polar bodies was close to 4% for each. Fourteen hyperploidies were found, seven involving additional single chromatids. The abnormalities affected chromosomes 13,16,18, 21 and X but not chromosomes 1, 9 or 12. CONCLUSION: The data provide evidence for several mechanisms leading to aneuploidy, including classical non-disjunction of whole univalents; pre-division of chromatids prior to anaphase I, leading to imbalance detected at metaphase II; gonadal mosaicism for a trisomic cell line and preferential involvement of the smaller chromosomes. Monosomy for the large autosomes is not uncommon in cleavage-stage embryos and may additionally arise from anaphase lag preferentially affecting such chromosomes.

Adult↗

PubMed2004

Prenatal search for UPD 14 and UPD 15 in 83 cases of familial and de novo heterologous Robertsonian translocations.

OBJECTIVES: The presence in the conceptus of a Robertsonian translocation predisposes to UPD formation, mainly by post-zygotic events of chromosome abnormality rescue. This is due to the increased risk of generating aneuploid zygotes because the rearranged chromosome and the respective homologues are prone to non-disjunction errors. Given this, carriers and karyotypically normal individuals conceived from a parent with a Robertsonian translocation are at risk for UPD. Abnormal phenotypes due to an imprinting effect have been found to be associated with UPD 14 and 15. The aim of the study was to refine, at the time of prenatal diagnosis, the risk for UPD 14 and 15 in a population with Robertsonian translocations involving these chromosomes. METHODS: Sixty-five cases of familial and de novo heterologous Robertsonian translocations involving chromosomes 14 and 15 and 18 fetuses with a normal karyotype, but conceived by a Robertsonian translocation carrier were prenatally studied to investigate the presence of UPD for chromosomes 14 and 15. RESULTS: Of the 65 Robertsonian translocation carriers, one fetus with a de novo der(14;21) showed maternal UPD 14. None of the 18 fetuses with a normal karyotype had UPD. CONCLUSION: Our data, combined with other previous prenatal investigations provide a general risk estimate for UPD 14 and 15 of 0.6%. Nevertheless, combining our data and those previously reported, all three fetuses with UPD had a de novo Robertsonian translocation, thus suggesting a risk of UPD formation of about 3% for this specific group of translocation carriers.

Amniotic Fluid↗

PubMed1995

A novel adenosine triphosphate analog with a heavy atom to target the nucleotide binding site of proteins.

We have synthesized 2'-deoxy-2'-iodoadenosine-5'-triphosphate (2'-IATP), a heavy-atom analog of adenosine-5'-triphosphate. This compound was made for X-ray structural studies to target the nucleotide site of ATP binding proteins. It was diffused successfully into crystals of the microtubule-based motor proteins ncd (non-claret disjunctional protein from Drosophila melanogaster) and kinesin. With ncd, the nucleotide binding site was 70% occupied and the crystals were able to diffract X-rays to 2.5 A. The iodo-analog provided a useful isomorphous derivative with overall phasing power 1.89 in the range of 25.0-2.5 A. With kinesin, 2'-IATP co-crystallized with the protein. The crystals diffracted to at least 2.8 A with a phasing power of 1.73 in the range of 20.0-5.0 A. The analog was also found to be a substrate for all of the enzymes tested, including creatine kinase, pyruvate kinase, hexokinase, and myosin, with values of Km and Vmax that were within a factor of 10 of those for ATP. The analog supported muscle contraction, relaxing fibers, and producing active tension with values not statistically different from those obtained with ATP. These results all suggest that this analog should be useful for providing a heavy-atom derivative for crystals of enzymes that bind ATP.

Adenosine Triphosphatases↗

PubMed2003

Effect of age on testicular germ cell apoptosis and sperm aneuploidy in MF-1 mice.

The spontaneous mutation rate in the male germ-line increases with age. The reason for this is unknown, but presumably involves an age-related degeneration in the efficacy of cellular processes. To investigate the possibility that rates of apoptosis and genetic damage (represented by aneuploidy) might vary with age in mice, the testes and sperm of 2- and 12-month-old male MF-1 mice were examined by a modified TUNEL technique and 3-colour sperm-FISH assay, respectively. Sperm were labeled with probes to chromosomes 8, X and Y and 20,000 sperm scored from each of 5 animals per group. A significant increase in gonosomal disomy was found in the aged mice, especially X-X-8. This suggests that advanced paternal age is associated primarily with meiosis II rather than meiosis I disjunction errors. Neither diploidy nor autosomal disomy was affected in the older group. The rate of germ cell apoptosis (apoptotic cells per seminiferous tubule cross-section per animal per group) was higher in the old mice than controls, but not significantly. Considerable inter-animal variability was observed in the older group. The finding of an increase in levels of sperm aneuploidy is novel for 1-year-old mice and confirms the genotoxic effect of ageing in mice. Since apoptosis is assumed to eliminate cells with unrepaired damage, it may be that the apoptotic response in older mice is compromised, resulting in the higher levels of aneuploidy in sperm. However, given the inter-animal variability in testicular germ cell apoptosis, this awaits confirmation.

Aging↗