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Uniparental disomy (UPD) in humans is caused primarily by meiotic nondisjunction events, followed by trisomy or monosomy 'rescue'. The majority of cases appear to be associated with advanced maternal age, and may be initially detected as mosaic trisomies during routine prenatal diagnosis by chorionic villus sampling or amniocentesis. In addition, structural abnormalities including Robertsonian translocations, reciprocal translocations and supernumerary marker chromosomes appear to be associated with an increased risk of UPD. Predicting the phenotypic effects of UPD is complex, as three independent factors are involved: (i) effects of trisomy on the placenta or the fetus; (ii) autosomal recessive disease due to reduction to homozygosity; and (iii) imprinted gene effects for some chromosomes. To date, UPD in humans has been reported for 25 of the 47 possible uniparental types. Imprinting effects have been established with certainty for four human chromosomes that have homology to mouse chromosomes which have been shown to have significant phenotypic effects in uniparental animals. A normal phenotype has been reported for 14 other UPD types. Thus, collection of data on UPD cases in humans is providing an imprinting map analogous to the experimentally derived imprinting map in mouse. This human imprinting map has important clinical implications, particularly in the area of prenatal diagnosis.
Hum Mol Genet 1995
PMID:Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis. 854 76

Ectrodactyly (split hand/split foot malformation, SHSF) is a human limb malformation characterized by absent central digital rays, deep median cleft, and syndactyly of remaining digits. The disorder is genetically heterogeneous, with at least two loci thus far determined: an autosomal locus at 7q21 designated SHFM1 and an X-linked locus at Xq26 designated SHFM2. Cytogenetic analysis of sporadic SHSF patients and linkage studies in extended pedigrees both suggest more than one autosomal locus exists. We report a novel SHSF locus suggested by a stillborn infant with ectrodactyly and other malformations who inherited an unbalanced translocation resulting in monosomy 4p15.1-4pter and trisomy for 10q25.2-qter. To investigate 10q25 as a possible split hand/split foot locus, microsatellite markers spanning 52 cM of 10q were utilized for linkage analysis of a large autosomal dominant SHSF pedigree in which the region encompassing SHFM1 previously was excluded as containing the causative mutation. The marker D10S583 was fully informative in the family, giving a maximum LOD score of 4.21 at recombination theta = 0.00. Recombination haplotypes define the 9 cM region between D10S541 and D10S574 as inclusive for this second autosomal SHSF locus, for which we propose the designation SHFM3.
Hum Mol Genet 1995 Nov
PMID:A second autosomal split hand/split foot locus maps to chromosome 10q24-q25. 858 97

In humans, the relationship between advancing maternal age and the incidence of trisomy has been long established, but the possible effect of increasing age of the father remains controversial. Using a fluorescence in situ hybridization (FISH) approach to directly examine individual sperm for aneuploidy of the sex chromosomes and chromosome 18, we have analyzed approximately 400,000 sperm from 24 men aged 18-60 years. There was no obvious relationship between increasing age and disomy 18, but the incidence of XY,YY and XX disomy all were significantly elevated among older men. This suggests that older men, like older women, have an increased likelihood of producing aneuploid offspring by comparison with their younger counterparts.
Hum Mol Genet 1995 Dec
PMID:Non-disjunction in human sperm: evidence for an effect of increasing paternal age. 863 91

Construction of animal models of human inherited diseases is particularly important for testing gene therapy approaches. Towards this end, we constructed a mouse model for Charcot-Marie-Tooth disease type 1A by pronuclear injection of a YAC containing the human PMP22 gene. In one transgenic line, the YAC DNA is integrated in about eight copies and the PMP22 gene is strongly expressed to give a peripheral neuropathy closely resembling the human pathology. The disorder is dominant, causes progressive weakness of the hind legs, and there is severe demyelination in the peripheral nervous system including the presence of onion bulb formations. This approach will be valuable for pathologies produced by over-expression of a gene including trisomy and amplification in cancer. Such models will be particularly useful for testing gene therapy approaches if the transgene is human.
Hum Mol Genet 1996 May
PMID:Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA. 873 21

Down syndrome is a common disorder affecting many tissues both during development and later on in adult life; the principle feature of all cases is a specific form of mental retardation, which is combined with a range of variable traits. Down syndrome is an aneuploidy syndrome that is caused by trisomy for human chromosome 21. While the phenotype is most likely due to a subtle increase in gene dosage of only a small minority of the estimated 500-800 genes that are present on this chromosome, the molecular genetics of Down syndrome remains speculative. However, recent advances on a number of fronts, including chromosome studies, gene identification and mouse modelling, are giving us the tools to dissect this multifactorial gene dosage disorder.
Hum Mol Genet 1996
PMID:Down syndrome genetics: unravelling a multifactorial disorder. 887 45

Parental age is the most important aetiological factor in trisomy formation in humans. Cytogenetic studies on germ cells reviewed here imply that (i) 2-4% sperm are aneuploid and 8.6% oocytes from IVF are hyperploid (ii) a paternal age effect may exist, and (iii) oocytes of aged women contain precociously separated chromatids in metaphase II. Trisomy data suggest that most aneuploidy is generated during meiosis I of oogenesis and is maternal age-dependent. Trisomy 18 is unique, originating mostly from maternal meiosis II errors. The extra gonosome in 47, XXY derives mostly from a paternal meiosis I error. Trisomy of individual chromosomes may remain low, linearly rise, or exponentially increase with advanced maternal age. Maternal age related trisomies involve achiasmatic and normochiasmate chromosomes, and chromosomes with disturbed recombination and distally located chiasmata. Hypotheses on the origin of the maternal age effect are critically reviewed. One model is presented that relates to altered cell cycle and protein phosphorylation in oocytes of aged mammals and accounts for most of the observed data in humans and in experimental studies. Aneuploidy may thus involve a predetermined component but is possibly also influenced by extrinsic factors reducing oocyte quality or depleting the oocyte pool precociously. Areas of future research are proposed to elucidate (i) the significance of early disturbances in the prenatal ovary, (ii) parameters diminishing the quality of oocytes in dictyate stage, and (iii) mechanisms enabling oocytes to process all chromosomal configurations successfully during later stages of oogenesis. Studies with newly developed and existing animal models appear indispensable to identify exposures affecting chromosome disjunction during meiosis, especially in the aging female.
Environ Mol Mutagen 1996
PMID:Parental age-related aneuploidy in human germ cells and offspring: a story of past and present. 890 81

A basic question concerning the origins of germ cell aneuploidy is whether the same mechanisms operate for all chromosomes, or whether there are chromosome-specific factors influencing the susceptibility to nondisjunction. Although selective loss of some trisomies in early gestation may contribute to the observed differences in trisomy frequency, data from spontaneous abortions, early embryos and gametes strongly suggest that there are real differences in the frequency with which different trisomies arise. In particular the preponderance of trisomy 16 and acrocentric trisomy appears to be present at conception. Maternal and paternal age relationships also differ among trisomies, as do the extent of maternal and paternal contributions, and the relative frequency of meiosis I and meiosis II errors. Recombination patterns associated with nondisjunction also show chromosomal differences. Chromosomal differences in length, centromere position, pericentromeric and other repetitive sequences, recombination patterns and chromatin characteristics might all be related to a differential susceptibility to aneuploidy, but no current explanation accounts for the excess of maternally derived trisomy 16. The existence of chromosome-specific factors makes extrapolation from observations on one chromosome to all aneuploidy unwise, both for investigations into the causes of aneuploidy, and for surveillance of aneuploidy frequency.
Environ Mol Mutagen 1996
PMID:Chromosomal differences in susceptibility to meiotic aneuploidy. 890 82

Trisomy in the human appears to be predominantly associated with maternal age. The maternal-age effect, however, shows considerable variability across affected chromosomes. Chromosome-specific variation has been reported in the shapes of the maternal-age-effect curves, including very small effects for the large chromosomes (groups A and B), linear increases (chromosome 16), and exponential increases (chromosome 21). There is also variation among chromosomes in whether the segregation errors occur predominantly at maternal meiosis I, meiosis II, and/or postfertilization mitotic divisions. There is also limited epidemiological evidence for a paternal-age effect, which was recently supported by the findings of age-related increases in sperm aneuploidy using fluorescence in situ hybridization methods. The paternal-age effect is considerably smaller than the maternal and is more likely to involve meiotic II errors of the sex chromosomes, whereas the maternal-age effect is more likely to arise from meiotic I errors producing autosomal trisomies. These and other differences suggest that constitutional aneuploidy arises by multiple mechanisms that may affect (1) the nature and timing of an initiating lesion affecting the oocyte or sperm; (2) the cellular physiology of the time of the nondisjunction event at meiosis I, II, or postfertilization; and (3) the selection against specific chromosomal aneuploidies during embryonic development. Multidisciplinary research is needed to understand the maternal and paternal-age effects on aneuploidy, to (1) identify and characterize the genes that control meiosis, recombination, and segregation; (2) identify the micro-environmental factors around the oocyte and mole germ cells that are involved in the age effects; (3) develop a laboratory animal model for the age effects; (4) characterize the role of genetics, physiology, and environmental toxicology for the paternal-age effects; and (5) identify cohorts of men and women of differing ages who have been exposed to high doses of candidate aneugens and conduct epidemiological investigations of aneuploidies transmitted to their offspring.
Environ Mol Mutagen 1996
PMID:Mechanisms and targets involved in maternal and paternal age effects on numerical aneuploidy. 890 84

Villous tissues from 30 spontaneous abortions and the same number of artificial abortions were obtained and analysed for the frequency of polyploid cells. Single cell suspensions were made from these tissues without culture and the ploidy of > 100 cells was analysed. Trisomies of chromosomes 17 and 4 have rarely been reported in villous cells of spontaneous abortions, suggesting that the presence of more than three copies of chromosomes 17 and 4 per cell indicates polyploidy. The number of chromosomes 17 and 4 was detected by fluorescence in-situ hybridization analysis using centromeric probes D17Z1 and D4Z1. Most villous cells from cases of spontaneous and artificial abortions had two D17Z1 or D4Z1 signals per cell, with very small percentages of cells (0.5 +/- 0.4%) showing three signals per cell. However, in four cases of spontaneous abortions, 2-12% of cells had three D17Z1 or D4Z1 signals per cell. This indicates the presence of triploid cells in these cases of spontaneous abortion, at a significantly higher frequency compared to artificial or the remaining 26 cases of spontaneous abortion. In addition, three cases contained 0.2-0.4% of cells showing six signals, indicating that these cells were dividing triploid cells. The low frequency of mosaicism reported here would not be detectable by conventional chromosomal analysis.
Mol Hum Reprod 1997 May
PMID:Direct assessment of triploid cells in mosaic human fetuses by fluorescence in-situ hybridization. 923 30

Duplications or deletions are present in a high percentage of the gametes produced by individuals carrying balanced translocations. Preimplantation genetic diagnosis was used to examine chromosome balance in embryos from a patient having a reciprocal translocation within the short arms of chromosomes 5 and 8 (46,XX,t(5;8)(p13;p23)). This woman has two sisters with the translocation unbalanced, resulting in a partial trisomy for chromosome 5 and partial monosomy for chromosome 8 (46,XX,-8, +der(8)t(5;8)(p13;p23)) with associated mental retardation and physical abnormalities. The patient and her husband desired to have children without the abnormal chromosome balance and wished to reduce the likelihood of spontaneous abortion or need for therapeutic abortion. Fluorescence in-situ hybridization (FISH) probes for the alpha-satellite region of chromosome 8 and for a region on the short arm of chromosome 5 (5p15.2) were tested initially on lymphocytes from the patient and her sisters. The hybridization signal for chromosome 5 was detected in the expected two copies for the patient and three copies for the sisters in 87% of the cells. Two hybridization signals for chromosome 8 were detected in 96% of the cells from all individuals. Additional probe testing was done using blastomeres from polyspermic embryos. The couple then proceeded with a stimulated in-vitro fertilization (IVF) cycle and biopsies were done on 13 embryos at the 7-10-cell stage using a method of zona drilling and fluid displacement. Diagnosis was possible on at least one blastomere for nine embryos. Three embryos had nuclei with three hybridization signals for chromosome 5, three had fewer than two signals for one or both chromosomes, one was mosaic, and two had two signals for each chromosome. The latter were transferred to the patient, but pregnancy was not achieved. The results demonstrate that preimplantation genetic diagnosis for patients with reciprocal translocations can be used to identify embryos having normal chromosome balance. The potential advantages and limitations of this approach are discussed.
Mol Hum Reprod 1998 Feb
PMID:Preimplantation genetic diagnosis of chromosome balance in embryos from a patient with a balanced reciprocal translocation. 954 75


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