Chromosomal translocations affecting 12q14-15 but not deletions of the long arm of chromosome 7 associated with a growth advantage of uterine smooth muscle cells.
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Cytogenetically, uterine leiomyomata are the best investigated human tumours. The most frequent clonal abnormalities are structural rearrangements involving 12q14-15 and deletions of part of the long arm of chromosome 7. The present study investigated a possible growth advantage conferred by these abnormalities, when compared with myomata having an apparently normal karyotype. A total of 155 myomata were included in the study. All samples were obtained after hysterectomy enabling karyotype analysis of all detectable tumours. Myomata with clonal chromosome abnormalities were significantly larger than those with a normal karyotype (6.8 +/- 5.3 versus 3.4 +/- 2.1 cm; P < 0.001). However, when differentiating between the two main aberrations, this was found to be true for the myomata with 12q14-15 changes affecting the high mobility group protein IC (HMGIC) gene (8.9 +/- 5.6 cm), but not for the group of tumours characterized by deletions of chromosome 7 (3.5 +/- 2.0 cm). The results are compatible with the hypothesis that myomata develop due to an unknown event, whereas the chromosomal abnormalities act as secondary changes, with those affecting the HMGIC gene increasing the growth potential of the corresponding tumours. (+info)
Normal genetically mosaic mice produced from malignant teratocarcinoma cells.
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Malignant mouse teratocarcinoma (or embryonal carcinoma) cells with a normal modal chromosome number were taken from the "cores" of embryoid bodies grown only in vivo as an ascites tumor for 8 years, and were injected into blastocysts bearing many genetic markers, in order to test the developmental capacities, genetic constitution, and reversibility of malignancy of the core cells. Ninety-three live normal pre- and postnatal animals were obtained. Of 14 thus far analyzed, three were cellular genetic mosaics with substantial contributions of tumor-derived cells in many developmentally unrelated tissues, including some never seen in the solid tumors that form in transplant hosts. The tissues functioned normally and synthesized their specific products (e.g., immunoglobulins, adult hemoglobin, liver proteins) coded for by strain-type alleles at known loci. In addition, a tumor-contributed color gene, steel, not previously known to be present in the carcinoma cells, was detected from the coat phenotype. Cells derived from the carcinoma, which is of X/Y sex chromosome constitution, also contributed to the germ line and formed reproductively functional sperms, some of which transmitted the steel gene to the progeny. Thus, after almost 200 transplant generations as a highly malignant tumor, embryoid body core cells appear to be developmentally totipotent and able to express, in an orderly sequence in differentiation of somatic and germ-line tissues, many genes hitherto silent in the tumor of origin. This experimental system of "cycling" teratocarcinoma core cells through mice, in conjunction with experimental mutagenesis of those cells, may therefore provide a new and useful tool for biochemical, developmental, and genetic analyses of mammalian differentiation. The results also furnish an unequivocal example in animals of a non-mutational basis for transformation to malignancy and of reversal to normalcy. The origin of this tumor from a disorganized embryo suggests that malignancies of some other, more specialized, stem cells might arise comparably through tissue disorganization, leading to developmental aberrations of gene expression rather than changes in gene structure. (+info)
Germline and gonosomal mosaicism in the ATR-X syndrome.
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We have identified two females who are mosaic for an ATRX mutation. One case, in whom the mutation was undetectable in peripheral blood and buccal cells, has two affected sons and is therefore presumed to be a germline mosaic. In another case, the ATRX mutation is weakly detectable in the peripheral blood but only one of her three children who share the disease-associated haplotype carries the mutation and therefore it is concluded that she is a gonosomal mosaic. These cases provide the first molecular evidence for the occurrence of post-zygotic mutation in X-linked alpha thalassaemia mental retardation syndrome. The possibility of germline mosaicism must therefore be considered in the genetic counselling of ATR-X families. (+info)
Quantitative analysis of cell allocation during liver development, using the spf(ash)-heterozygous female mouse.
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Mosaicism of ornithine transcarbamylase (OTC) expression in hepatocytes was quantitatively analyzed during liver development of the spf(ash)-heterozygous female mouse. Because the mosaic patterns depend on cell migration and cell mixing, such analysis could give insights on the growth pattern or allocation pattern of hepatocytes during liver development. Complex mosaic patterns of OTC-positive and -negative hepatocytes were observed in sections of fetal and postnatal livers. Sizes of patches, which were aggregates of OTC-positive or -negative hepatocytes, increased during development. Patches were slender and comparatively simple in 15.5- and 17.5-day fetal and neonatal livers. Quantitative analysis of patch shapes demonstrated that undulation of patches was maximal at 7 postnatal days. Patches with nodular shapes also started to increase in number at this stage. Isolated patches in sections of fetal livers and postnatal livers three-dimensionally connected with one another. However, especially in fetal livers, in which OTC-positive patches were minor, due to the presence of abundant hemopoietic cells, isolated three-dimensional patches consisting of approximately 5 to 70 cells were often found. They were shaped like slender branching or zigzag-shaped cords, but no definite orientation such as portal-central was observed in them at any stage. These results suggest that hepatocytes contiguously allocate their daughter cells as zigzag-shaped or branching cords at younger stages. Some hepatocytes grow with nodular formation after 7 postnatal days. Migration and mixing of hepatocytes appear to be more extensive at fetal stages than in the adult liver. Immunohistochemical analysis of intercellular junction proteins (E-cadherin, connexins 26 and 32, occludin, and ZO-1) also revealed that their expression and distribution changed in hepatocytes during development, which may be correlated with the OTC mosaic patterns. (+info)
Targets of TGF-beta signaling in Caenorhabditis elegans dauer formation.
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Caenorhabditis elegans dauer formation is controlled by multiple environmental factors. The chemosensory neuron ASI regulates dauer formation by secretion of DAF-7/TGF-beta, but the molecular targets of the DAF-7 ligand are incompletely defined and the cellular targets are unknown. We genetically characterized and cloned a putative transducer of DAF-7 signaling called daf-14 and found that it encodes a Smad protein. DAF-14 Smad has a highly unusual structure completely lacking the N-terminal domain found in all other Smad proteins known to date. daf-14 genetically interacts with daf-8, which encodes another Smad, and the interaction suggests partial functional redundancy between these two Smad proteins. We also studied the cellular targets of DAF-7 signaling by studying the sites of action of daf-14 and daf-4, the putative receptor for DAF-7. daf-14::gfp is expressed in multiple tissues that are remodeled during dauer formation. However, analysis of mosaics generated by free duplication loss and tissue-specific expression constructs indicate cell-nonautonomous function of daf-4, arguing against direct DAF-7 signaling to tissues throughout the animal. Instead, these experiments suggest the nervous system as a target of DAF-7 signaling and that the nervous system in turn regulates dauer formation by other tissues. (+info)
De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10.
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Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by deletion of most copies of the 3.3-kb subtelomeric D4Z4 repeat array on chromosome 4q. The molecular mechanisms behind the deletion and the high proportion of new mutations have remained elusive. We surveyed 35 de novo FSHD families and found somatic mosaicism in 40% of cases, in either the patient or an asymptomatic parent. Mosaic males were typically affected; mosaic females were more often the unaffected parent of a nonmosaic de novo patient. A genotypic-severity score, composed of the residual repeat size and the degree of somatic mosaicism, yields a consistent relationship with severity and age at onset of disease. Mosaic females had a higher proportion of somatic mosaicism than did mosaic males. The repeat deletion is significantly enhanced by supernumerary homologous repeat arrays. In 10% of normal chromosomes, 4-type repeat arrays are present on chromosome 10. In mosaic individuals, 4-type repeats on chromosome 10 are almost five times more frequent. The reverse configuration, also 10% in normal chromosomes, was not found, indicating that mutations may arise from transchromosomal interaction, to which the increase in 4-type repeat clusters is a predisposing factor. The somatic mosaicism suggests a mainly mitotic origin; mitotic interchromosomal gene conversion or translocation between fully homologous 4-type repeat arrays may be a major mechanism for FSHD mutations. (+info)
Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents.
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von Hippel-Lindau disease (VHL [MIM 193300]) is a heritable autosomal dominant multiple-neoplastic disorder with high penetrance. It is characterized by brain and spinal-cord hemangioblastomas, retinal angiomas, clear-cell renal carcinoma, neuroendocrine tumors and cysts of the pancreas, pheochromocytomas, endolymphatic-sac tumors, and papillary cystadenomas of the epididymis and broad ligament. Although most index cases have a positive family history of VHL, some do not and may represent de novo cases. Cases without a family history of VHL may or may not have a germline mutation in their VHL tumor-suppressor gene. We present two cases of VHL mosaicism. In each of two families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL-gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, the 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the disease have been reported in as many as 23% of kindreds with VHL. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult disease. (+info)
The zebrafish colourless gene regulates development of non-ectomesenchymal neural crest derivatives.
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Neural crest forms four major categories of derivatives: pigment cells, peripheral neurons, peripheral glia, and ectomesenchymal cells. Some early neural crest cells generate progeny of several fates. How specific cell fates become specified is still poorly understood. Here we show that zebrafish embryos with mutations in the colourless gene have severe defects in most crest-derived cell types, including pigment cells, neurons and specific glia. In contrast, craniofacial skeleton and medial fin mesenchyme are normal. These observations suggest that colourless has a key role in development of non-ectomesenchymal neural crest fates, but not in development of ectomesenchymal fates. Thus, the cls mutant phenotype reveals a segregation of ectomesenchymal and non-ectomesenchymal fates during zebrafish neural crest development. The combination of pigmentation and enteric nervous system defects makes colourless mutations a model for two human neurocristopathies, Waardenburg-Shah syndrome and Hirschsprung's disease. (+info)