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PubMed1995

Mosaicism: the embryo as a target for induction of mutations leading to cancer and genetic disease.

Mosaicism, the existence of "patches" of cells with a genetic constitution that differs from that of other cells of an organism, has been observed in both germinal and somatic tissues of several species, including humans. Mutational events occurring during early embryogenesis can give rise to an organism with a significant number of cells with the mutant genotype in one or more tissues. If this event occurs in a precursor of the germ cells, the mutation can be transferred to subsequent generations. In the F1 generation, this event will usually be perceived as a de novo germinal mutation rather than a transmitted variant allele, unless significant effort is directed toward detecting the mosaicism. Similarly, mutations in oncogenes and tumor-suppressor genes in proliferating somatic cells can generate populations of cells that are at increased risk of transforming into tumor cells. The number of potential preneoplastic cells is larger when the mutagenic event occurs in early development than if it occurs in the mature adult. Experimental data confirm that treatment of the developing embryo or fetus with carcinogenic and mutagenic agents increases the cancer incidence in these animals and the frequency of mutations in the offspring of the animals that were exposed in utero. The available data are conclusive that the developing organism is at risk from exposure to mutagenic and carcinogenic agents. However, the data are insufficient to estimate the level of risk associated with exposures in utero, relative to either the background (spontaneous) level of risk or risk associated with similar exposures to the adult organism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

An evaluation of the reactivity of the card agglutination test for trypanosomiasis (CATT) reagent in the Fontem sleeping sickness focus, Cameroon.

The TestrypR Card Agglutination Test for Trypanosomiasis (CATT) used for the serodiagnosis of gambiense trypanosomiasis is based on the variant antigen type (VAT) LiTat 1.3. This antigen is rarely expressed by trypanosomes in the Fontem focus of Cameroon, but the CATT has been used for serodiagnosis in the focus since 1985. We give here a summary of results obtained with the CATT in Fontem from 1985 to 1989. The CATT is specific for trypanosome antibodies since: (a) sera from persons with other parasitoses from areas non endemic for trypanosomiasis fail to react and (b) an enzyme-linked immunosorbent assay (ELISA) based on the detection of antibodies to somatic antigens of T.b gambiense from Fontem concorded with the CATT. CATT reactions in Fontem seem to be specific for the variant surface glycoprotein (VSG) since absorption of CATT reactive sera with formalin fixed bloodstream T. gambiense from Fontem and with culture produced procyclics of T. gambiense from Fontem failed to abrogate CATT reactivity. CATT on serum failed to confirm 37% of CATT positive cases on whole blood. Although immunoconglutinin (IK), anti-human red blood cell (RBC) antibodies and complement fixing immune complexes (ICs) were found in sera from Fontem, our results failed to incriminate immunoconglutination of RBCs, reactions of RBCs with their autoantibodies and immune adherence hemagglutination as contributory factors in this lack of agreement between CATT on serum and whole blood. Further, comparison of whole blood and serum CATT results of parasitologically confirmed patients leads to the conclusion that screening with the CATT in the Fontem focus should be done on whole blood, not serum or plasma. CATT reactions in Fontem are based on cross-reactions with as yet undefined VATs.

Adolescent↗
PubMed1988

Stable variant of LM fibroblast defective in fluid-phase but competent in receptor-mediated endocytosis.

The F-40 cell line, a stable variant of LM fibroblasts selected for its resistance to polyethylene glycol (PEG)-induced fusion (Roos and Davidson: Somatic Cell and Molecular Genetics 6:381-391, 1980), has a decreased capacity to internalize fluid-phase markers and nonspecifically surface-bound macromolecules. It is not defective in exocytosis since, after a short sucrose pulse, it releases the same fraction of ingested sucrose into the medium as does the parental line. F40 cells have a normal capacity to carry out receptor-mediated endocytosis, as tested with 125I-alpha-2 macroglobulin (alpha-2 MG) and 125I-transferrin (Tf), and to recycle Tf receptor to the cell surface. These data demonstrate that receptor-mediated and non-receptor mediated endocytosis are distinct processes that can be altered independently. Of the many membrane fusions occurring in the course of endocytosis, the only one that appears associated with the defect in cell fusion characteristic of F40 cells is the formation of primary endocytotic vesicles engaged in non-receptor-mediated internalizations.

Animals↗
PubMed1996

Isolation and characterization of human hepatoma cells with targeted insertions of a gpt selectable marker in the alpha 1-antitrypsin locus.

The bacterial xanthine-guanine phosphoribosyl transferase (gpt) gene was inserted by homologous recombination into the chromosomal alpha 1-antitrypsin (alpha 1AT) gene of HPRT-deficient human hepatoma cells. These insertions encoded chimeric alpha 1AT-gpt mRNAs that were expressed in the modified cells. Six targeted integrations were obtained, but only two of these harbored simple insertion events. The remaining four homologous insertions contained additional DNA sequences 3' of the gpt coding cassette. Variant cell lines deficient for gpt expression were isolated from transfectants containing either homologous or non-homologous gpt insertions by selection in media containing 6-thioguanine. These variant cell lines expressed alpha 1AT but not alpha 1AT-gpt mRNAs, indicating that they contained expression defects in cis. Genotypic analyses suggested that the predominant mechanism by which the variants were generated was by nondisjunctive loss of chromosomes containing the modified alpha 1AT-gpt alleles. Somatic cell hybrids formed by fusing hepatoma cells containing targeted alpha 1AT-gpt insertions with fibroblasts exhibited extinction of both modified and unmodified alpha 1AT alleles.

Base Sequence↗
PubMed2006

Heteroplasmy as a common state of mitochondrial genetic information in plants and animals.

Plant and animal mitochondrial genomes, although quite distinct in size, structure, expression and evolutionary dynamics both may exhibit the state of heteroplasmy--the presence of more than one type of mitochondrial genome in an organism. This review is focused on heteroplasmy in plants, but we also highlight the most striking similarities and differences between plant and animal heteroplasmy. First we summarize the information on heteroplasmy generation and methods of its detection. Then we describe examples of quantitative changes in heteroplasmic populations of mitochondrial DNA (mtDNA) and consequences of such events. We also summarize the current knowledge about transmission and somatic segregation of heteroplasmy in plants and animals. Finally, factors which influence the stoichiometry of heteroplasmic mtDNA variants are discussed. Despite the apparent differences between the plant and animal heteroplasmy, the observed similarities allow one to conclude that this condition must play an important role in the mitochondrial biology of living organisms.

Animals↗
PubMedDate not supplied

Structural and serological analysis of cross-reactive idiotypes: comparison of heavy and light chain families of anti-arsonate antibodies.

The amino acid sequences of VH and VL regions of 16 cross-reactive idiotype-positive (CRI+) and ten CRI-negative (CRI-) monoclonal anti-arsonate antibodies from a range of laboratories were compared. Analysis of the data demonstrates the existence of several pairs of hybridoma proteins (within CRI+ and CRI- families) which have identical or very similar sequences for VH and VL. This strongly suggests the existence of at least 4 germ-line genes in A/J mice coding for CRI+VH, CRI+VL, CRI-VH and CRI-VL regions. The CRI+ family, however, consists of VH structures which represent either (1) germ-line sequences, (2) VHVL variants with a few substitutions, or (3) VHVL variants with extensive substitutions. The latter two consist of antibodies which have lost either the CRI or arsonate binding capacities. The CRI- family consists of two very different groups. The first group appears to be the product of CRI- VHVL germ-line genes and their variants. The second group contains antibodies coded by CRI+ germ-line genes but which, due to somatic diversification, become CRI-. Comparison of VHVL of all anti-arsonate antibodies clearly indicates that light chain selection by the heavy chain is a non-random process. Also, there appears to be a parallel diversification of VH and VL. Comparative data on H and L chain structures and serological evidence obtained by three monoclonal antiidiotypic antibodies indicates that formation of the original cross-reactive idiotypic determinant(s) requires an equal contribution for both H and L chains; moreover, CRI consists of a single (or few) idiotopes.

Amino Acid Sequence↗
PubMedDate not supplied

Nucleotide sequence evidence for rapid genotypic shifts in the bovine mitochondrial DNA D-loop.

Mitochondrial DNA (mtDNA) is unusual in its rapid rate of evolution and high level of intraspecies sequence variation. The latter is thought to be related to the strict maternal inheritance of mtDNA, which effectively isolates within a species mitochondrial gene pools that accumulate mutations and vary independently. A fundamental and as yet unexplained aspect of this process is how, in the face of somatic and germ-line mtDNA ploidy of 10(3) to 10(5) (refs 4, 5), individual variant mtDNA molecules resulting from mutational events can come to dominate the large intracellular mtDNA population so rapidly. To help answer this question, we have determined here the nucleotide sequence of all or part of the D-loop region in 14 maternally related Holstein cows. Four different D-loop sequences can be distinguished in the mtDNA of these animals. One explanation is that multiple mitochondrial genotypes existed in the maternal germ line and that expansion or segregation of one of these genotypes during oogenesis or early development led to the rapid genotypic shifts observed.

Animals↗
PubMed2006

Requirement of hCenexin for proper mitotic functions of polo-like kinase 1 at the centrosomes.

Outer dense fiber 2 (Odf2) was initially identified as a major component of sperm tail cytoskeleton and later was suggested to be a widespread component of centrosomal scaffold that preferentially associates with the appendages of the mother centrioles in somatic cells. Here we report the identification of two Odf2-related centrosomal components, hCenexin1 and hCenexin1 variant 1, that possess a unique C-terminal extension. Our results showed that hCenexin1 is the major isoform expressed in HeLa cells, whereas hOdf2 is not detectably expressed. Mammalian polo-like kinase 1 (Plk1) is critical for proper mitotic progression, and its association with the centrosome is important for microtubule nucleation and function. Interestingly, depletion of hCenexin1 by RNA interference (RNAi) delocalized Plk1 from the centrosomes and the C-terminal extension of hCenexin1 was crucial to recruit Plk1 to the centrosomes through a direct interaction with the polo-box domain of Plk1. Consistent with these findings, the hCenexin1 RNAi cells exhibited weakened gamma-tubulin localization and chromosome segregation defects. We propose that hCenexin1 is a critical centrosomal component whose C-terminal extension is required for proper recruitment of Plk1 and other components crucial for normal mitosis. Our results further suggest that the anti-Odf2 immunoreactive centrosomal antigen previously detected in non-germ line cells is likely hCenexin1.

Amino Acid Sequence↗
PubMed2004

Understanding germ-line mutations in BRCA1.

Germ-line mutations in BRCA1 account for the majority of familial breast and ovarian cancer cases and development of cancer in individuals who carry such mutations requires somatic inactivation of the normal allele. BRCA1 is highly polymorphic with more than 1,200 distinct documented variants. Approximately 70% of reported variants lead to absence of full-length BRCA1 protein, through loss of expression or protein truncation, and are suspected to predispose to cancer. These include regulatory mutations, splice site alterations, large rearrangements, large and small deletions or insertions, and nonsense mutations. However, characterizing the remaining missense alterations as either deleterious (cancer-associated mutations) or neutral variants is more complex, as the functional significance of the respective amino acid substitution is not straightforward to evaluate. In addition, many missense variants have been identified only once in defined ethnic groups and represent alleles with very low frequency. Most often, little information is available about segregation of the variant with disease in families, and assessment of disease risk for low frequency alleles through association studies is problematic, requiring a large number of samples stratified and matched by ethnicity. The fact that a significant proportion of BRCA1 variants remain unclassified represents a gap in risk assessment, such that individuals undergoing genetic testing will receive noninformative test results. An approach for assessing the potential clinical significance of missense variants is to combine available genetic data with functional and structural studies. Here we review the available information on BRCA1 variants and explore ways in which we can analyze unclassified variants.

BRCA1 Protein↗
PubMed2000

Biallelic inactivating mutations and an occult germline mutation of PTEN in primary cervical carcinomas.

A tumor suppressor gene on chromosome sub-band 10q23.3, PTEN, is frequently mutated or deleted in a variety of human cancers. Germline mutations in PTEN, that encodes a dual-specificity phosphatase, have been implicated in two hamartoma-tumor syndromes that exhibit some clinical overlap, Cowden syndrome and Bannayan-Zonana syndrome. Although cervical cancer is not a known component of these two syndromes, loss of heterozygosity (LOH) of markers on chromosome arm 10q is frequently observed in cervical cancers. To determine the potential role that PTEN mutation may play in cervical tumorigenesis, we screened 20 primary cervical cancers for LOH of polymorphic markers within and flanking the PTEN gene, and for intragenic mutations in the entire coding region and exon-intron boundaries of the PTEN gene. LOH was observed in 7 of 19 (36.8%) cases. Further, one sample may have homozygous deletion. Three (15%) intragenic mutations were found: two were somatic missense mutations in exon 5, that encodes the phosphatase motif, and an occult germline intronic sequence variant in intron 7, that we show to be associated with aberrant splicing. All three samples with the mutations also had LOH of the wild-type allele. These data indicate that disruption of PTEN by allelic loss or mutation may contribute to tumorigenesis in cervical cancers. In cervical cancer, unlike some other human primary carcinomas, e.g., those of the breast and thyroid, biallelic structural PTEN defects seem necessary for carcinogenesis. Further, one in 20 unselected cervical carcinomas was found to have a germline PTEN mutation; it is unclear whether the patient with this mutation had Cowden disease or a related syndrome.

Adenocarcinoma↗
PubMed1998

A phosphoglycerate kinase mutant (PGK Herlev; D285V) in a Danish patient with isolated chronic hemolytic anemia: mechanism of mutation and structure-function relationships.

Phosphoglycerate kinase (PGK) is a X-linked enzyme that plays a key role in the glycolytic pathway. Twelve different variants have already been reported. We describe a new PGK variant, PGK Herlev (Asp 285-->Val), in a 69-year-old Danish patient with isolated chronic hemolysis but who had no neurological or muscular disorders. The description of the mutation is based upon PCR amplification of specific regions of the PGK gene, followed by direct sequencing. Although observed in a male patient, this mutated X-linked gene is expressed partially, i.e., both normal and substituted nucleotides are present at the same position in a ratio of approximately 1:9. The most likely explanation for this observation is based on the occurrence of a somatic mutation of the PGK gene. The relationship of structure to function in PGK Herlev, as well as in all known variants, was examined by the use of a computer model based on the known spatial structure of the yeast and horse enzymes. Such an approach can be generalized to any other protein that has been crystallized and for which x-ray diffraction data are available in a species closely related to man.

Aged↗
PubMed1988

Alternative V kappa gene rearrangements in a murine B cell lymphoma. An explantation for idiotypic heterogeneity.

Idiotype variants of 38C13, a murine B cell lymphoma, have been isolated by immunoselection with antiidiotype mAbs. The V region genes for the kappa light chains and mu heavy chains expressed by these tumor cells were sequenced and compared. There was no evidence for V region somatic point mutation in this tumor. However, while the heavy chain genes were all identical, the light chain genes were all different. The light chain genes of each variant were derived from the V kappa-Ox1 gene family and joined to J kappa 4, whereas the light chain gene of the parental tumor was derived from the V kappa 9 family and joined to J kappa 2. Two of the variants used the identical V kappa gene but differed by the inclusion of a variable number of additional nucleotides in the V/J joint. Thus, the idiotypic heterogeneity of this B cell lymphoma arises as a consequence of alternative light chain rearrangements rather than point mutation. This process repetitively uses members of the same V kappa gene family. Two of the variants use the identical V kappa and J kappa gene segments but differ by the presence of extra nucleotides at the V kappa/J kappa joint.

Amino Acid Sequence↗
PubMed2002

Expression of a novel HsMCAK mRNA splice variant, tsMCAK gene, in human testis.

Identification of specifically expressed genes in the adult or fetal testis is very important for the study of genes related to the development and function of the testis. In this study, a human adult testis cDNA microarray was constructed and hybridized with 33P-labeled human adult and embryo testis cDNA probes, respectively. After differential display analyzing, a number of new genes related to the development of testis and spermatogenesis had been identified. One of these new genes is tsMCAK. tsMCAK was expressed 2.62 folds more in human adult testis than fetal testis. The full length of tsMCAK is 2401 bp and contains a 2013 bp open reading frame, encoding a 671-amino-acid protein. Sequence analysis showed that it has a central kinesin motor domain and is homologous to HsMCAK gene of the somatic cells. Blasting human genome database localized tsMCAK to human chromosome 1P34 and further investigation showed that it is a splice variant of HsMCAK. The tissue distribution of tsMCAK was determined by RT-PCR and it is expressed highly and specifically in the testis. Southern blot studies of its expression in patients with infertility indicated its specific expression in spermatogenic cells and its correlation with male infertility. The above results suggested that tsMCAK is a candidate gene for the testis-specific KRPs and its specific expression in the testis was correlated with spermatogenesis and may be correlated with male infertility.

Adult↗
PubMed2003

Inherited variants in MYH are unlikely to contribute to the risk of lung carcinoma.

The base excision repair gene MYH protects against damage to DNA from reactive oxygen species, which are commonly found in cigarette smoke. Inherited mutations in MYH predispose to colorectal adenomas and carcinomas that show a characteristic pattern of somatic G:C-->T:A mutations in the APC gene. A similar pattern of somatic mutations in the TP53 gene is reported in smoking-related lung cancers. We therefore tested whether germline changes in MYH may also contribute to the development of lung cancer by screening for variants in 276 patients with lung carcinoma and 106 normal controls. No patients harboured truncating mutations in MYH and only a single patient was a carrier for the G382D missense mutation. We identified three common coding region (V22M, Q324H and S501F) and intronic (157+30A>G, 462+35G>A and 1435-40G>C) variants, but none were over-represented in the patient samples, indicating that MYH variants are unlikely to predispose significantly to the risk of lung cancer.

Adenocarcinoma↗
PubMed2003

High gradient magnetic cell sorting and internal standardisation substantially improve the assay for somatic mutations at the glycophorin A (GPA) locus.

In the MACS-BR6 version of the GPA assay [Int. J. Radiat. Res. 70 (1996) 131] variant red blood cells (RBC) are isolated from 5 x 10(8) normal RBC by magnetic cell separation (MACS) before detection and quantification by immunolabelling and flow cytometry as in the classical BR6 assay. In the present work it is described how the MACS-BR6 assay is improved by internal standardisation with FITC-labelled RBC. This modification of the assay has the advantage that (i) the analysis of variants is not disturbed by the overwhelming number of normal RBC that (ii) the precision of the assay is improved and finally that (iii) a sufficient number of variants is available for further investigations. Tn positive RBC behave in MACS like variants. It is demonstrated that in normal individuals Tn cells (frequency: approximately 2 x 10(-8)) do not disturb the assay.

Adult↗
PubMed1994

[Study of the membrane expression of TcR/CD3 complex using somatic cell mutants].

T lymphocytes express membrane antigen receptor TcR/CD3 complexes only when all subunits are correctly assembled. Studies on TcR/CD3 membrane negative T cell variants containing all necessary subunits intracellularly, may allow to identify amino acids important for different subunit interactions. In this review, we summarize our recent work on TcR/CD3 negative variants of the human T cell line Jurkat. We found two critical amino acids in the TcR-alpha and TcR-beta extracellular constant regions (phenylalanine n. 216 and intrachain disulfide cysteine n. 212) involved in TcR-alpha beta/CD3- gamma epsilon, delta epsilon intermediary complex/zeta 2 homodimer interactions: (1) amino acid exchanges of phenylalanine demonstrated the importance of an aromatic amino acid residue at this position; (2) the intrachain disulfide bond assures a tertiary structure of the constant domain that is necessary for association with zeta 2 homodimers.

Amino Acid Sequence↗
PubMed2001

Mitochondrial DNA alteration in esophageal cancer.

It has been reported that various cancers frequently have mutations in the D-loop region of mitochondrial DNA (mtDNA). We examined the genetic alterations in this region of esophageal cancer using direct sequencing. Of 68 sequence variants, 15 have not been reported to date. Tumor mtDNA with these variants were compared with mtDNA from corresponding normal esophageal mucosa. Two of 37 primary esophageal cancers (5%) contained somatic mutations in the D-loop region of mtDNA. Although the mutation rate of mitochondrial tumor DNA within the D-loop was not high, this result suggested that mtDNA mutations play a role in the development of esophageal cancer.

DNA Mutational Analysis↗
PubMed2001

Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene.

Maintenance of genomic methylation patterns in mammalian somatic cells depends on DNA methyltransferase-1 (Dnmt1). Mouse oocytes and preimplantation embryos lack Dnmt1 but express a variant of this protein called Dnmt1o. We eliminated Dnmt1o by deletion of the oocyte-specific promoter and first exon from the Dnmt1 locus. Homozygous animals were normal, but most heterozygous fetuses of homozygous females died during the last third of gestation. Although genomic methylation patterns were established normally in Dnmt1o-deficient oocytes, embryos derived from such oocytes showed a loss of allele-specific expression and methylation at certain imprinted loci. Transient nuclear localization of Dnmt1o in 8-cell embryos suggests that this variant of Dnmt1 provides maintenance methyltransferase activity specifically at imprinted loci during the fourth embryonic S phase.

Animals↗