Familial structural chromosome abnormality with maternal mosaicism.
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The method of directed modification of damaged DNA regions elaborated recently in our laboratory made it possible to conduct a direct experimental study of mutagenicity of two single-stranded breaks located within the isolocus of sister chromatids, in strands of the same polarity. The efficiency of induced mutagenesis was shown to be very high when the experimental technique was employed allowing single-stranded DNA breaks to occur in this position with high probability. It should be noted that the fraction of interstitial deletions and rearrangements of chromosomes of the exchange type were predominant in the spectrum of induced mutations. It is concluded that the coincidence of two breaks in the strands of the same polarity in the isolocus of sister chromatids is realised into chromosome aberrations with high probability.
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Cessation of exchange interactions among chromosomes and change of the chromosome type of aberrations for chromatid type were found on the model of the Crepis capillaris germinating seeds sychronized with 5-fluor-2-desoxyuridine at the end of G1-beginning of S-phase and then exposed to X-ray irradiation.
The level of chromosomal aberrations in cultured blood lymphocytes from patients with hyperplasia, atypical hyperplasia of endometrium and endometrial cancer was studied. Chromosomal aberration frequency significantly increased up to 5.000 +/- 00.47% in patients with atypical and endometrial hyperplasia and to 5.21 +/- 00.53% in patients with endometrial cancer in comparison to 0.67 +/- 0.21% in the control. All indices were more pronounced in endometrial cancer patients with pathology in pedigree.
Thrombopoietin (TPO), the ligand for c-mpl, is a novel cytokine comprising an amino terminal domain with homology to erythropoietin and a glycosylated carboxyl terminal domain that does not bear overall homology to other known proteins. We report the cloning of cDNAs encoding the porcine and murine TPO and the characterization of the human TPO gene. The cDNA for an additional splice form (TPO-2) with a four-amino-acid deletion within the erythropoietin-like domain has been isolated and is conserved between humans, pigs, and mice. Species comparison of TPO shows that the amino terminal erythropoietin-like domain is highly conserved, while the carboxyl terminal domain is less conserved. Recombinant murine TPO and human TPO are each able to activate both the murine and human c-mpl receptors, indicating an absence of strict species specificity. Human TPO is encoded by a single gene consisting of six exons and located on chromosome 3q27-28.
The genotoxic activity of 2-methyl aminothiadiazole and azo dyes series of azo thiadiazole-1,3,4 was assessed using chromosome aberration in vivo and in vitro. The test in vivo was performed on mice bone marrow cells and in vitro on human blood lymphocytes. Derivatives of 2-naphthol, p-chlorophenol, pyro-catechin, resorcin and gamma resorcin acid were tested. The study did not reveal any toxic effect of azo dies in doses used in the test. Their use in the synthesis of more complex substances can be recommended.
Isolation and characterization of cDNAs encoding human very low density lipoprotein (VLDL) receptor revealed the presence of two forms of the receptor: one consists of five domains that resemble the low density lipoprotein (LDL) receptor, and a variant form lacks an O-linked sugar domain. More than 96% of amino acids in the human and rabbit VLDL receptors are identical, whereas those in the LDL receptors are less conserved between the two species (76%). The human VLDL receptor gene contains 19 exons spanning approximately 40 kilobases. The exon-intron organization of the gene is almost the same as that of the LDL receptor gene, except for an extra exon that encodes an additional repeat in the ligand binding domain of the VLDL receptor. Analysis of DNA from human-rodent hybrid cells revealed that the gene is located on chromosome 9. Although the 5'-flanking region of the VLDL receptor gene contains two copies of a sterol regulatory element-1 like sequence, the levels of mRNA for the receptor in THP-1 human monocytic leukemia cells were unchanged by sterols. The 5'-untranslated region of the receptor mRNA contains a polymorphic triplet repeat found also in the fragile X syndrome gene.
As to the authors' data 73% of women who gave birth to children with Down's syndrome (DS) (191 out of 231) were younger than 35 years. In this "young" group 191 couples were examined caryologically, 9 individuals having balanced translocations and 4 persons having mosaicism with a little trisomic clone were revealed. Mean ages of these parents are 24.3 for women and 32.5 for men. The rate of chromosome aberrations is 1.95% that is 8 times higher than in general population of newborns. 0.85% of examinees had heavy detectable mosaicism. Hence, no less than 5.6% of families with DS child, that are not subjected to a prenatal diagnostics because of young age, have different chromosome aberrations causing high risk of birth of an abnormal child.
We previously identified a gene, reg (i.e. regenerating gene), in the screening of a regenerating islet-derived cDNA library of rat (Terazono, K., Yamamoto, H., Takasawa, S., Shiga, K., Yonemura, Y., Tochino, Y., and Okamoto, H. (1988) J. Biol. Chem. 263, 2111-2114), and isolated a human reg cDNA and gene (Watanabe, T., Yonekura, H., Terazono, K., Yamamoto, H., and Okamoto, H. (1990) J. Biol. Chem. 265, 7432-7439); the rat and human cDNAs encode 165- and 166-amino acid proteins, respectively. Until now, it was thought that there is a single locus for Reg protein in the mammalian genome. In this study, we isolated two distinct cDNAs and genes, one of which was a mouse homologue to rat and human reg gene, the other a novel type of reg gene. We designated them reg I and reg II, respectively. The two proteins encoded by these genes share 76% amino acid sequence identity with each other. Both genes span about 3 kilobase pairs, and the genomic organization of six exons and five introns is conserved between them. Chromosomal mapping studies indicate that the reg I gene is localized on mouse chromosome 12, whereas the reg II gene is localized on chromosome 3. By Northern blot analysis, both reg I and reg II mRNAs are detected in the normal pancreas and hyperplastic islets of aurothioglucose-treated mice, but not in the normal islets. It is remarkable that in the gallbladder reg I is expressed, but reg II is not.
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