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PubMed1984

c-myc and immunoglobulin kappa light chain constant genes are on the 8q+ chromosome of three Burkitt lymphoma lines with t(2;8) translocations.

We have determined the localization of c-myc and the immunoglobulin kappa light chain genes on the 8q+/2p- chromosomes of the three Burkitt lymphoma lines BL21, LY66 and LY91 with t(2;8) translocation by in situ hybridization. BL21 is characterized by a complex translocation in which a piece of chromosome 9 appears to be located between the fragments of chromosome 8 and 2 on the 8q+ chromosome. Our data indicate that in all three cell lines the c-myc gene is located on the 8q+ chromosome proximal to the breakpoint in band 8q24. In all cell lines examined the cluster of kappa variable genes has remained on the 2p- chromosome. In LY91 cells the major part of the joining region remained on 2p-, while the joining region has moved to 8q+ in the cell lines BL21 and LY66. In all three cell lines the constant kappa light chain gene was found on the 8q+ chromosome. The fact that an essentially identical pattern was found in the cell line BL21, with the complex translocation, suggests that the insertion of the piece of chromosome 9 into the 8q+ chromosome might be a secondary event. Our present data fit into the concept that in all Burkitt lymphoma lines investigated so far, including cases with t(8;14) and the variant translocations t(2;8) and t(8;22), the c-myc gene becomes situated at the 5' side of an immunoglobulin constant gene. This may have implications for the generation of somatic mutations in the coding and non-coding part of the c-myc gene.

Burkitt Lymphoma↗
PubMed1992

Development of a flow-cytometric HLA-A locus mutation assay for human peripheral blood lymphocytes.

A flow-cytometric technique was developed to measure the frequency of variant lymphocytes lacking expression of HLA-A2 or A24 allele products among donors heterozygous for HLA-A2 or A24. It was found that the variant frequency of lymphocytes in peripheral blood was of the order of 10(-4) and increased with donor age. Molecular analyses of mutant clones revealed that about one-third were derived from somatic recombinations and that the remaining two-thirds did not show any alterations after Southern blotting analysis. In contrast, mutants obtained after in vitro X-ray mutagenesis study were found to be mostly derived from large chromosomal deletions. A small-scale study on atomic bomb survivors did not show a significant dose effect.

Adult↗
PubMed2005

The 2p21 deletion syndrome: characterization of the transcription content.

The vast majority of small-deletion syndromes are caused by haploinsufficiency of one or several genes and are transmitted as dominant traits. We have previously identified a homozygous deletion of 179,311 bp on chromosome 2p21 as the cause of a unique syndrome, inherited in a recessive mode, consisting of cystinuria, neonatal seizures, hypotonia, severe somatic and developmental delay, facial dysmorphism, and reduced activity of all the respiratory chain enzymatic complexes that are encoded in the mitochondria. We now present the transcription content of this region: Multiple splicing variants of the genes protein phosphatase 1B (formerly 2C) magnesium-dependent, beta isoform (PPM1B), SLC3A1, and KIAA0436 (approved gene symbol PREPL) were identified and their patterns of expression analyzed. The spliced variants are predicted to have additional functions compared to the known variants and their patterns of expression fit the tissues affected by the syndrome. The first exon of an additional gene (C2orf34) is encoded in the deleted region and the gene is not expressed in the patients. In addition several transcripts with very short open reading frames are also encoded in the deletion. The identification of all transcripts encoded in the region deleted in the patients is the first step in the study of the genotype-phenotype correlation of the 2p21 patients.

Alternative Splicing↗
PubMed1997

Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL.

Inherited predisposition to phaeochromocytoma (MIM No 171300) occurs in multiple endocrine neoplasia type 2 (MEN 2) (MIM No 171400), von Hippel-Lindau (VHL) disease (MIM No 199300), and neurofibromatosis type 1 (NF1) (MIM No 162200). In addition, familial phaeochromocytoma alone has also been reported and we and others have identified germline VHL mutations in five of six kindreds analysed previously. Germline mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, and in the VHL tumour suppressor gene cause MEN 2 and VHL disease, respectively. To further investigate the genetics of phaeochromocytoma predisposition, we analysed three groups of patients with no evidence of VHL disease, MEN 2 or NF1: Group A, eight kindreds with familial phaeochromocytoma; Group B, two patients with isolated bilateral phaeochromocytoma; and Group C, six cases of multiple extra-adrenal phaeochromocytoma or adrenal phaeochromocytoma with a family history of neuroectodermal tumours. Germline missense VHL mutations were identified in three of eight kindreds with familial phaeochromocytoma. A germline VHL mutation was also characterised in one of the two patients with bilateral phaeochromocytoma. No VHL or RET mutations were detected in the final group of patients with multiple extra-adrenal phaeochromocytoma or adrenal phaeochromocytoma with a family history of neuroectodermal tumours. The absence of germline VHL and RET gene mutations in many of these families suggested that other phaeochromoeytoma susceptibility loci may exist. Glial cell line-derived neurotrophic factor (GDNF) has been recently identified as a natural ligand for RET. Thus, it seems plausible that GDNF is a good candidate gene to play a role in phaeochromocytoma susceptibility. We searched for germline mutations in GDNF in 16 cases of familial phaeochromocytoma (groups A, B and C) and looked for evidence of somatic change in GDNF in 28 sporadic phaeochromocytomas, 12 MEN 2 phaeochromocytomas and five VHL phaeochromocytomas. No GDNF mutations were identified in patients with familial phaeochromocytoma disease, but a c277C-->T (R93W) sequence variant was identified in one of 28 sporadic tumours. This candidate mutation was identified in the germline and tumour tissue but was not present in 104 control GDNF alleles. GDNF sequence variants including R93W have been suggested previously to represent low penetrance susceptibility mutations for Hirschsprung disease and the R93W was not identified in 376 control alleles studied by others. These findings suggest that although GDNF mutations do not appear to have a major role in the pathogenesis of familial or sporadic phaeochromocytomas, allelic variation at the GDNF locus may modify phaeochromocytoma susceptibility.

Adrenal Gland Neoplasms↗
PubMed2025

Moss BRCA2 lacking the canonical DNA-binding domain promotes homologous recombination and binds to DNA.

BRCA2 is crucial for mediating homology-directed DNA repair (HDR) through its binding to single-stranded DNA (ssDNA) and the recombinases RAD51 and DMC1. Most BRCA2 orthologs have a canonical DNA-binding domain (DBD) with the exception of Drosophila melanogaster. It remains unclear whether such a noncanonical BRCA2 variant without DBD possesses a DNA-binding activity. Here, we identify a new noncanonical BRCA2 in the model plant Physcomitrium patens (PpBRCA2). We establish that PpBRCA2 is essential for genome integrity maintenance, somatic DNA double-strand break (DSB) repair, HDR-mediated gene targeting, and RAD51 foci recruitment at DNA break sites. PpBRCA2 is also critical for DSB repair during meiosis. Interestingly, PpBRCA2 interacts strongly with RAD51 but weakly with DMC1, suggesting a distinct meiotic function compared to other BRCA2 homologs. Despite lacking the canonical DBD, PpBRCA2 binds ssDNA through its disordered N-terminal region and efficiently promotes HDR. Our work highlights that the ssDNA binding capacity of BRCA2 homologs is conserved regardless of the presence of a canonical DBD and provides a deeper understanding of BRCA2's functional diversity across species.

BRCA2 Protein↗
PubMed1985

[Ischemic diseases of the lower limbs].

On the material of 200 necropsies and 230 surgically amputated lower extremities in patients with an acute obstruction of the main arteries as well as the study of the limb muscles in the appropriate experimental models, the principal rules and the pathogenesis of the muscle damage in the ischemic disease of the lower extremities (IDLE) are described. Four clinico-anatomical variants of the acute IDLE are distinguished: (1) diffuse degenerative-necrotic muscle damage; (2) large-focal necrosis; (3) massive isolated necrosis of single muscles; (4) limb gangrene. Grave general and local somatic background in a patient, causes of death and role of the IDLE in thanatogenesis are characterized.

Acute Disease↗
PubMed2005

[Clinical variants of hypochondriac state in patients with duodenal ulcer].

AIM: To describe some clinical variants of hypochondriac syndrome in patients with duodenal ulcer (DU). MATERIAL AND METHODS: A hypochondriac trend was studied clinically and was confirmed by changes in the first scale of AMPI in 150 DU patients. If the first scale contained a rise over 70 points, the examinee was stated to be much concerned about his/her health. RESULTS: Hypochondriac syndrome in exacerbation was registered in 59 (39.3%) patients. It was accompanied with anxiety in 28.8% cases. Introversion and original attitude to somatic disorders were observed in 25.4% cases. Demonstrative behavior was seen in 23.8% patients. Depressive trends occurred in 13.5% patients. Conception of the disease was confirmed in 5.1% cases. Hypochondriac state with protest reactions and hyperthymic effect occurred least frequently (1 and 1 case, respectively). CONCLUSION: Hypochondriac states aggravate DU, deteriorate quality of life. Early diagnosis of a variant of hypochondriac syndrome enables a directed individual psychotherapy which improves emotional state of the patient and prevent further development of psychopathological traits.

Anxiety Disorders↗
PubMedDate not supplied

[Long-term effects of chronic radiation exposure on the level of somatic mutations in peripheral blood cells].

The level of comatic mutations was studied at GPA locus and in the TCR system at late times since the onset of radiation exposure in persons exposed to chronic radiation accidents at the Mayak Production Association in the period 1949-1952. Individuals with predominantly external gamma-exposure and those with predominantly internal (mainly due to 90Sr) exposures have been identified among the exposed population. The average dose to red bone marrow made up 121.5 cSv with individual values ranging from 11.0 to 462.7 cSv. An increased frequency of TCR-mutant lymphocytes was noted for exposed subjects. The level of GPA-variant erythrocytes of different types in the study group did not differ from the respective value registered in control. The analysis of TCR status showed no dependence of mutant cell frequency on exposure dose. The assumption is made that the rate of exposure dose and the nature of its formation (chronic exposure) exert a decisive influence on the level of somatic mutations in peripheral blood cells in humans.

Glycophorins↗
PubMed1983

Development of a screening system for detection of somatic mutations. II. The use of peptides and insoluble protein fragments in a non-competitive solid-phase enzyme immunoassay.

A system proposed for measurement of mutational risk consists in detection of hemoglobin mutations expressed in erythrocytes. For this detection the production of antibodies specific for Hb variants is essential. Recently we reported a sensitive solid-phase EIA for the production and selection of polyclonal and monoclonal antibodies specific for hemoglobin determinants. An important characteristic of this EIA was the coating of water-insoluble proteins to polystyrene microtiter plates. Here we report that with this system, insoluble protein fragments and small peptides may also be covalently coated to a polystyrene surface. Coating is independent of the length of the peptides. This allows direct, non-competitive titration of the antibody response to small peptides and avoids the drawbacks of competitive assay.

Animals↗
PubMed1977

Expression of genes for metabolism of cyclic adenosine 3':5'-monophosphate in somatic cells. beta-Adrenergic and PGE1 receptors in parental and hybrid cells.

Using the ligands [125I]iodohydroxybenzylpindolol and [3H]prostaglandin E1 ([3H]PGE1), we have studied the relationship of receptors for beta-adrenergic agents and for PGE1 to adenylate cyclase in membranes of parental, hybrid, and variant mammalian cell lines. Fusion of parental clones responsive to beta-adrenergic agonists (beta+) with unresponsive clones (beta-) produced hybrid clones with a greatly diminished beta-adrenergic response; beta+ X beta leads to beta-. Binding studies with [125I]iodohydroxybenzylpindolol showed a decreased concentration of beta receptors in six such hybrid clones. Thus, paucity of beta-adrenergic receptors is probably a sufficient, albeit not necessarily complete, explanation for the decreased beta-adrenergic responsiveness of the hybrid clones. When a clone with beta receptor but without apparent adenylate cyclase activity (HC-1) was hybridized with a beta- clone that has adenylate cyclase (B82), a responsive hybrid clone was obtained. In nine cell hybrids produced by the fusion of clones responsive (PGE1+) and unresponsive (PGE1-) to PGE1, high affinity binding sites for [3H]PGE1 were expressed in the same manner as was PGE1-sensitive adenylate cyclase: PGE1+ X PGE1 leads to PGE1+. The chemical specificities and affinities of the parental receptors and responsive adenylate cyclases were faithfully reproduced in the hybrid clones. Activation by PGE1 was proportional to the occupation of the high affinity receptors. In a wild type lymphoma clone (24.3.2), the concentration dependences for binding of [3H]PGE1 and for activation of adenyalte cyclase by PGE1 were identical. In a variant lymphoma clone (94.15.1) lacking adenylate cyclase activity, no high affinity receptors for PGE1 were detected, whereas beta-adrenergic receptors have been demonstrated in this variant clone (Insel, P.A., Maguire, M.E., Gilman, A.G., Coffino, P., Bourne, H., and Melmon, K. (1976) Mol. Pharmacol. 12, 1062-1069). Hybrid cells formed by the fusion of 94.15.1 with cell line RAG (PGE1-) responded to PGE1. Clone 94.15.1 may have receptors for PGE1 of reduced affinity or in low concentration. Alternatively, RAG and 94.15.1 may have complementary genetic defects such that the RAG X 94.15.1 hybrid cells express a hormonally responsive receptor-adenylate cyclase system.

Adenylyl Cyclases↗
PubMed1988

Hypogonadotrophic variant of Klinefelter's syndrome. A case report.

A 16-year-old boy with 47,XXY chromosomal complement (Klinefelter's syndrome) presented with delayed puberty and apparent gonadotrophin deficiency. Despite an inadequate growth hormone response to insulin-induced hypoglycaemia and to L-dopa administration, his somatic growth was appropriate for his delay in pubertal development, increasing markedly on testosterone treatment. Patients with Klinefelter's syndrome may have abnormalities of neuro-endocrine regulation.

Adolescent↗
PubMed1998

Somatic mutations in LKB1 are rare in sporadic colorectal and testicular tumors.

Germ-line mutations in a serine/threonine kinase gene, LKB1, were recently shown to underlie Peutz-Jeghers syndrome (PJS), a hereditary disorder that predisposes to benign and malignant tumors of multiple organ systems. Most mutations that have been described thus far dramatically change the predicted protein and are likely to be of an inactivating nature. This observation and a previous observation that the LKB1 locus is often deleted in PJS polyps suggest that the gene may function as a tumor suppressor. We examined whether somatic mutations in this gene are present in sporadic carcinomas of the colon and testis, tumors that are characteristic of PJS. First, 20 randomly selected colorectal and 28 testicular tumors were analyzed by single-strand conformation polymorphism analysis. No mutations in LKB1 were found in colorectal tumors. One testicular tumor displayed a heterozygous missense type variant, in which glycine 163 was changed to aspartic acid. This change was absent in the DNA of normal tissue. To better focus our efforts, we tested 75 additional colon carcinomas for loss of heterozygosity at 19p, where LKB1 is localized. Of 75 samples analyzed, 50 were informative with a closely linked marker, D19S886, and 13 (26%) of these displayed loss of heterozygosity. The 13 tumors were scrutinized for LKB1 mutations by genomic sequencing. This analysis revealed no changes. Together, these findings suggest that somatic mutations of LKB1 are not frequent in colorectal and testicular cancer.

AMP-Activated Protein Kinase Kinases↗
PubMed2004

BRAF gene is somatically mutated but does not make a major contribution to malignant melanoma susceptibility: the Italian Melanoma Intergroup Study.

PURPOSE: Ocogenic activation of the BRAF gene has been demonstrated to be involved in the pathogenesis of malignant melanoma (MM). In this study, we investigated the contribution of BRAF to melanoma susceptibility, also making a comparison with frequency of CDKN2A germline mutations in MM patients from different areas in Italy. PATIENTS AND METHODS: sing a combination of denaturing high-performance liquid chromatography analysis and automated sequencing on genomic DNA from peripheral blood or tumor tissue samples, 569 MM patients (211 from northern Italy and 358 from southern Italy) were screened for BRAF mutations. RESULTS: Three BRAF germline sequence variants (M116R, V599E, and G608H) were identified in four (0.7%) of 569 MM patients. The most common BRAF mutation, V599E, was detected in one germline DNA sample only; M116R and G608H were newly described mutations. A high frequency (59%) of BRAF mutations was instead observed in tumor samples from patients also undergoing germline DNA analysis; at the somatic level, substitution of valine 599 was found to account for the majority (88%) of BRAF mutations. We then estimated the germline mutation rates in BRAF and CDKN2A among 358 consecutively collected patient samples originating in southern Italy; a low (2.5%) or very low (0.29%) prevalence of CDKN2A and BRAF mutations, respectively, was detected. CONCLUSION: utation analysis of either blood DNA from a large collection of MM patients or matched MM tissues from a subset of such patients revealed that BRAF is somatically mutated and does not play a major role in melanoma susceptibility. The present study further suggests that patient origin may account for different mutation rates in candidate genes.

Adolescent↗
PubMed1993

Germ cell neoplasms of the testis.

Testicular germ cell neoplasia, a disease predominantly of young men, is, for unknown reasons, increasing in incidence. Cryptorchidism, a prior testicular germ cell tumor, a family history of testicular germ cell tumors, and somatosexual ambiguity syndromes remain well-established risk factors. Intratubular germ cell neoplasia of the unclassified type represents the common precursor to the great majority of testicular germ cell tumors, and its identification in testicular biopsies reliably identifies those patients who will often progress to an invasive lesion. Seminoma appears to represent the invasive derivative of intra-tubular germ cell of neoplasia of the unclassified type; problematic variants include seminomas with tubular, granulomatous, and edematous patterns. Spermatocytic seminoma is an essentially nonmetastasizing neoplasm unless complicated by the rare development of a sarcomatous component. Embryonal carcinomas usually occur admixed with other germ cell tumor types. The combination of positivity for placental alkaline phosphatase and negativity for epithelial membrane antigen can assist in the distinction of embryonal carcinomas from somatic carcinomas. The treatment of clinical stage I patients with nonseminomatous germ cell tumor with "surveillance only" may be contraindicated depending on features that include the proportion of embryonal carcinoma and the presence of lymphovascular invasion in the orchiectomy specimen. It is important to be aware that pure, mature teratomas in postpubertal patients may be associated with metastases of teratomatous or nonteratomatous type Yolk sac tumor is characterized by numerous patterns including glandular, myxomatous, sarcomatoid, hepatoid, and parietal variants. Choriocarcinomas classically have a biphasic pattern of syncytiotrophoblast and cytotrophoblast; trophoblastic proliferations lacking a biphasic pattern also occur but are difficult to classify unless this category is broadened. Mixed germ cell tumors, consisting of two or more different elements, are quite common. The polyembryoma is a distinctive, well-organized form of mixed germ cell tumor consisting of embryonal carcinoma and yolk sac tumor.

Choriocarcinoma↗
PubMed2004

Genetic and epigenetic screening for gene alterations of the chromatin-remodeling factor, SMARCA4/BRG1, in lung tumors.

The SMARCA4/BRG1 gene product is a component of the SWI-SNF chromatin-remodeling complex and regulates gene expression by disrupting histone-DNA contacts in an ATP-dependent manner. Inactivating mutations of the SMARCA4 gene, on chromosome arm 19p, are present in several human cancer cell lines, including cell lines derived from lung cancers. Interestingly, loss of heterozygosity (LOH) at 19p and absence of the SMARCA4 protein have been reported in lung tumors. To evaluate further the possible contribution of SMARCA4 gene inactivation to lung carcinogenesis, we performed a complete analysis of the SMARCA4 gene to search for (a) point mutations in all 35 coding exons, including an existing splicing variant and the intron-exon boundaries, and (b) abrogation of gene expression through promoter hypermethylation by using the methylation-specific polymerase chain reaction (MSP) assay. We selected genomic DNA from 20 lung primary tumors with LOH on 19p for the screening of point mutations and 10 lung cancer cell lines and 52 lung primary tumors for the MSP analysis. Through our mutational screening, we identified an in-frame and germ-line insertion of 24 bp in exon 4 whose biological relevance is unknown. This variant was not detected in the germ line of the 62 additional individuals analyzed, indicating it is not a common polymorphism. Moreover, two missense alterations were identified in the tumors of 2 patients, a somatic Gly1160Arg mutation and a Ser1176Cys mutation. Neither was present in the germ line of the 51 additional lung cancer individuals tested. Because these mutations lead to substitution of highly conserved amino acids, they may affect the ATPase function of the protein. Finally, no promoter hypermethylation was observed in any lung primary tumor or cancer cell line, indicating that this is not a major mechanism for SMARCA4 inactivation during lung carcinogenesis. In conclusion, our data revealed that somatic point mutations of the SMARCA4 gene are present in a small subset of lung tumors, although mutations affecting the ATPase domain may be a hot-spot for SMARCA4 gene inactivation. We cannot rule out that other mechanisms, such as complete or partial deletions of the SMARCA4 gene, are contributing to the loss of the SMARCA4 protein in lung cancer.

Amino Acid Sequence↗
PubMed2002

The nature and destiny of translocated B-chromosome-specific satellite DNA of rye.

Translocations of A chromosome-specific and B chromosome-specific satellite DNA were tracked by fluorescence in situ hybridisation from an irradiated M1 generation of an experimental population of rye (Secale cereale L.) to its M2 progeny. Although high frequencies of large structural rearrangements were detected in root-tip meristems of M1 plants, none was present at meiosis or in somatic cells of their progeny. These results are interpreted in terms of efficient "filtering" of translocations during vegetative development, and not in the more usual terms of meiosis presenting a physical barrier to structural variants. These observations highlight the fact that B-A translocations are not tolerated, and may explain why this form of chromosome mutation is largely absent from natural populations.

Chromosome Mapping↗
PubMed1990

Genotypic variation within asexual lineages of Taraxacum officinale.

Restriction site variation in DNA that encodes rRNA (rDNA) was surveyed among 714 offspring within 31 lineages (26 genotypes) of obligate asexually reproducing Taraxacum officinale (dandelions). Although clonal offspring are expected, plants with nonparental rDNA were produced from two parents that were themselves siblings (same genotype). The variation is best characterized by the loss of an EcoRI restriction site that maps to the spacer region in the parental rDNA and is most likely involved in amplification of rare or unique rDNA repeats. In one family, 41 surveyed offspring lacked the EcoRI site. In the other family, only 1 of 26 offspring lost the EcoRI site. Other classes of DNA surveyed, chloroplast DNA and the alcohol dehydrogenase 2 gene (Adh2), showed no variation. However, offspring with nonparental rDNA also had nonparental alcohol dehydrogenase 1 (Adh1) restriction fragments. Because somatic mutations in plants can be incorporated into reproductive tissue, we propose that somatic events affecting at least both multicopy rDNA and DNA homologous to the maize Adh1 gene occurred at different developmental times in the two families. An event early in development would result in all variant offspring; an event late in development would result in a single variant offspring. These results support the view that mutation (in the broad sense) influences the level of genotypic variation in asexual organisms, which may facilitate adaptive evolution of asexual species.

Alcohol Dehydrogenase↗
PubMed1983

Impact of genetic manipulation on society and medicine.

Human beings have been manipulating the genetic characteristics plants and animals since the introduction of agriculture indirect manipulation of human genes occurred with widespread use of public health and medical measures that preserve genes causing disease. The production of biologicals by DNA technology raises few ethical problems. Predictive medicine in which genetic markers (including DNA variants) are used for antenatal and preclinical diagnosis of genetic diseases and susceptibilities poses new questions of confidentiality, private versus societal goals, and self-determination. When normal DNA is used to treat the somatic cells of patients with hemoglobinopathies and other genetic diseases, no new ethical problems arise beyond those presented by an novel theory. In contrast, manipulation of DNA in human fertilized eggs would constitute a qualitative departure from previous therapies since this would affect future generations. In order to be able to make wise decisions on these matters the public must be well informed. Thus, formal and informal education in human biology and genetics must be improved at all levels.

Animals↗