Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Somatic variant”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources
PubMed1989

Suppression of aryl hydrocarbon hydroxylase activity in human primary lung carcinoma x mouse hepatoma somatic cell hybrids.

Variants of the mouse hepatoma cell clone inducible for aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH) (EC 1. 14. 14.1) activity and deficient in hypoxanthine guanine phosphoribosyl-transferase (EC 2.4.2.8), and human primary lung carcinoma cell clone noninducible for AHH activity and deficient in thymidine kinase (EC 2.7.1.21) were isolated. The variant lines characterized for AHH inducibility and drug resistant phenotype were utilized to study somatic cell hybrids for the expression of AHH induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In two hybrids AHH activity was not expressed. In view of these results we conclude that aryl hydrocarbon hydroxylase activity is suppressed in AHH noninducible human lung carcinoma x AHH inducible mouse hepatoma cell hybrids.

Animals↗
PubMed1991

Molecular mediators and events associated with attenuated MHC class I gene expression.

Numerous examples of altered expression of MHC class I antigens by cells with a malignant phenotype have been described. Of particular interest in this regard has been the description of neoplastic cells with attenuated class I antigen expression. The model system used in this laboratory for understanding the molecular mediators and events associated with attenuation in MHC class I gene expression enlists the use of Abelson virus transformed leukemia cells from which H-2 surface null variants have been immunoselected. For these variants, interdiction in MHC antigen expression occurs at many levels of eukaryotic gene regulation. The regulated expression of H-2 antigens from these somatic cell variants is discussed in relationship to the mechanisms of attenuated MHC class I gene expression described for other leukemias.

Abelson murine leukemia virus↗
PubMed1993

Identification through overexpression and tagging of the variant type of the mouse H1e and H1c genes.

Multiple, nonallelic forms of histone H1 are found in most mammalian tissues. Attempts to determine a functional significance to this diversity is hindered by a paucity of primary amino acid sequence data. Although numerous H1 genes have been cloned, the type of variant they encode cannot be determined by sequence analysis alone. We used transformation and overexpression methods to determine that two cloned mouse H1 genes, MH143 and MH175, encode H1c and H1e, respectively. Since these genes have been completely sequenced, these results establish the amino acid sequence of these variants. Assignment was accomplished by mutagenically "tagging" the genes by incorporation of a codon for methionine, which is not found in the major somatic H1 variants. These genes were placed under the control of the mouse metallothionein I promoter and introduced into 3T3 cells. Products of these mutagenized genes were detected by [35S]methionine labeling and identified by high performance liquid chromatography and sodium dodecyl sulfate-acid polyacrylamide gel electrophoresis. We were also able to induce major alterations in the normal stoichiometry of chromatin-associated H1 variants through overproduction of H1c and H1e. This had little effect on the growth properties of these transformants.

3T3 Cells↗
PubMed1997

Homopolymeric tract heteroplasmy in mtDNA from tissues and single oocytes: support for a genetic bottleneck.

While mtDNA polymorphisms at single base positions are common, the overwhelming majority of the mitochondrial genomes within a single individual are usually identical. When there is a point-mutation difference between a mother and her offspring, there may be a complete switching of mtDNA type within a single generation. It is generally assumed that there is a genetic bottleneck whereby a single or small number of founder mtDNA(s) populate the organism, but it is not known at which stages the restriction/amplification of mtDNA subtype(s) occur, and this uncertainty impedes antenatal diagnosis for mtDNA disorders. Length polymorphisms in homopolymeric tracts have been demonstrated in the large noncoding region of mtDNA. We have developed a new method, T-PCR (trimmed PCR), to quantitate heteroplasmy for two of these tracts (D310 and D16189). D310 variation is sufficient to indicate clonal origins of tissues and single oocytes. Tissues from normal individuals often possessed more than one length variant (heteroplasmy). However, there was no difference in the pattern of the length variants between somatic tissues in any control individual when bulk samples were taken. Oocytes from normal women undergoing in vitro fertilization were frequently heteroplasmic for length variants, and in two cases the modal length of the D310 tract differed in individual oocytes from the same woman. These data suggest that a restriction/amplification event, which we attribute to clonal expansion of founder mtDNA(s), has occurred by the time oocytes are mature, although further segregation may occur at a later stage. In contrast to controls, the length distribution of the D310 tract varied between tissues in a patient with heteroplasmic mtDNA rearrangements, suggesting that these mutants influence segregation. These findings have important implications for the genetic counselling of patients with pathogenic mtDNA mutations.

Animals↗
PubMed1988

Differences in the binding of H1 variants to DNA. Cooperativity and linker-length related distribution.

A study of the complexes formed between short linear DNA and three H1 variants, a typical somatic H1, and the extreme variants H5, from chicken erythrocytes, and spH1 from sea urchin sperm, has revealed differences between H1, H5 and spH1 that have implications for chromatin structure and folding. 1. All three histones bind cooperatively to DNA in 35 mM NaCl forming similar, but not identical, rod-like complexes. With sufficiently long DNA the complexes may be circular, circles forming more easily with H5 and spH1 than with H1. 2. The binding of H5 and spH1 to DNA is cooperative even in 5 mM NaCl, resulting in well-defined thin filaments that appear to contain two DNA molecules bridged by histone molecules. In contrast, H1 binds distributively over all the DNA molecules in 5 mM NaCl, but forms short stretches similar in appearance to the thin filaments formed with H5 and spH1. Rods appear to arise from the intertwining of regular thin filaments containing cooperatively bound histone molecules on raising the NaCl concentration to 35 mM. 3. The compositions of the rods correspond to one histone molecule for about every 47 bp (H1), 81 bp (H5) and 112 bp (spH1), suggesting average spacings of 24 bp (H1), 41 bp (H5) and 56 bp (spH1) in the component thin (double) filaments. Strikingly, these values are proportional to the linker lengths of the chromatins in which the particular H1 variant is the main or sole H1.

Animals↗
PubMed1990

Structural characterization of idiotopes by using antibody variants generated by site-directed mutagenesis.

Four anti-idiotopic mAB, 107, MB, AI, and AD8, react with mouse hybridoma protein 36-65 specific for the hapten p-azophenylarsonate. The four antiidiotypic antibodies do not react with hybridoma protein 36-71, a somatically mutated variant of 36-65 whose H and L chain V region sequence differs at 19 amino acid positions. To determine which regions of 36-65 are important for the interaction with each of the four anti-idiotypic antibodies, variants of 36-65 containing one or more of the 36-71 substitutions were generated by oligonucleotide-directed mutagenesis of the rearranged 36-65 H chain V region gene, followed by expression of mutant proteins containing either the 36-65 or the 36-71 L chain in transfected hybridoma cells. Idiotypic characterization of the mutant proteins showed that reactivity correlates with the 36-65 H chain, but some contributions from the 36-65 L chain come into play. In the 36-65 H chain V region, idiotopes were mapped to the first and third complementarity-determining regions for anti-idiotypic antibodies 107, MB, and AI, and to all three complementarity-determining regions for anti-idiotypic antibody AD8. The binding of all four anti-idiotypic antibodies to hybridoma protein 36-65 was hapten inhibitable. However, a comparison between the effect of individual 36-71 substitutions on idiotope expression and their effect on Ag-binding affinity suggests that none of the four anti-idiotypic antibodies bodies mimics the structure of Ag.

Amino Acid Sequence↗
PubMed2026

Costello Syndrome Associated With Somatic Mosaicism of Rare p.Gly13Asp HRAS Variant: Expanding the Phenotypic Spectrum.

BACKGROUND: Costello syndrome (CS) is a rare RASopathy, mostly caused by de novo heterozygous pathogenic variants in the HRAS gene. Over 80% of cases involve the germline p.Gly12Ser variant, resulting in a fairly uniform phenotype of neuro-cardio-facio-cutaneous involvement with an increased risk of malignancy. Consequences of other rare HRAS variants are less well understood due to the limited number of reported cases. METHODS: An adult, young woman was referred due to sparse, slow-growing scalp hair, Blaschko-linear hyperpigmentation, acanthosis nigricans, palmoplantar hyperkeratosis, and joint hyperlaxity. Molecular, imaging, and detailed laboratory studies were performed. RESULTS: Although initial clinical exome- and whole-exome sequencing (WES) were inconclusive, indicating possible mosaicism, subsequent WES from hair-derived DNA samples revealed somatic mosaicism for the rare HRAS p.Gly13Asp variant. Brain MRIs showed a cerebral cavernoma, while cardiological evaluation, urinalysis, abdominal, and pelvic ultrasound were unremarkable. Nevertheless, she remains under close follow-up. CONCLUSION: Among the ten reported individuals carrying the p.Gly13Asp variant, our patient is only the second with confirmed mosaicism and the fifth mosaic CS case described to date. This case expands the phenotypic spectrum of CS and highlights the need for multi-tissue analysis in attenuated or atypical presentations to ensure a correct diagnosis, oncological risk assessment, and informed genetic and reproductive counseling.

Humans↗
PubMed1982

Immunoglobulin V region variants in hybridoma cells. I. Isolation of a variant with altered idiotypic and antigen binding specificity.

The hybridoma cell line B1-8.delta 1 expresses an IgD antibody with specificity for the hapten 4-hydroxy-3-nitro-phenylacetyl (NP). Two monoclonal antibodies, each recognizing an idiotypic determinant (idiotope) in the variable region of antibody B1-8, and fluorescence-activated cell sorting were used for the isolation of spontaneous somatic cell variants whose antibody product lacks the expression of one of the two idiotopes. The variant cells carry a mutation which is expressed in the variable region of the antibody heavy chains and which reduces the affinity of the antibody for hapten greater than 100-fold. Idiotope loss variants of the selected phenotype are present in the B1-8.delta 1 cell population at low frequency.

Animals↗
PubMed1991

Somatic mutations in the variable regions of a human IgG anti-double-stranded DNA autoantibody suggest a role for antigen in the induction of systemic lupus erythematosus.

The processes that govern the generation of pathogenic anti-DNA autoantibodies in human systemic lupus erythematosus (SLE) are largely unknown. Autoantibodies may arise as a consequence of polyclonal B cell activation and/or antigen-driven B cell activation and selection. The role of these processes in humoral autoimmunity may be studied by molecular genetic analysis of immunoglobulin (Ig) variable (V) regions of antibodies that are characteristic of SLE. We have analyzed the gene elements that encode a high affinity, IgG anti-double-stranded DNA autoantibody secreted by a monoclonal Epstein-Barr virus (EBV)-transformed cell line derived from a patient with active SLE. In addition, we have identified, cloned, and sequenced the germline counterparts of the VH and VL genes expressed in this autoantibody. The comparison of both sets of gene elements shows that the autoantibody VH and VL regions harbor numerous somatic mutations characteristic of an antigen-driven immune response. The light chain expressed in this autoantibody is a somatically mutated variant of the kv325 germline gene that is frequently associated with paraproteins having autoantibody activity and with Ig molecules produced by malignant B cells that express the CD5 antigen. Furthermore, the utilized DH segment has been repeatedly found in multireactive, low affinity IgM anti-DNA autoantibodies from SLE patients and healthy individuals. These results suggest that pathogenic IgG anti-DNA autoantibodies in human SLE may arise through antigen-driven selection of somatic mutations in the gene elements that frequently encode multireactive IgM autoantibodies.

Amino Acid Sequence↗
PubMed1995

Chicken oocytes and somatic cells express different splice variants of a multifunctional receptor.

An abundant 95-kDa protein belonging to the low density lipoprotein receptor supergene family is essential for chicken oocyte growth by mediating the uptake of multiple plasma-borne yolk precursors. This receptor harbors at the amino terminus a cluster of eight tandemly arranged repeats typical of the ligand binding domains of members of this family and is designated low density lipoprotein receptor relative with 8 repeats (LR8). Here, we demonstrate by reverse transcriptase-polymerase chain reaction, Northern, and Western blot analyses that the chicken expresses two forms of LR8, which are generated by differential splicing of an exon encoding a serine- and threonine-rich region characteristic of LRs, termed O-linked sugar domain. The female germ cell of the chicken expresses extremely high levels of the short form of LR8 (LR8-), i.e. the 95-kDa protein; in contrast, somatic cells express lower but detectable levels of the form containing the O-linked sugar domain (LR8+). The main sites of LR8+ expression in the chicken are the heart and skeletal muscle, i.e. the same tissues were LR8 mRNAs predominate in mammals; in addition, in situ hybridization demonstrates that a significant amount of LR8+ is produced in the hen's ovarian follicular granulosa cells. We found no apparent functional difference between the two receptor forms; however, cell type-specific targeting of the multiple ligands of these receptors possibly relates to their respective expression on the cell surface.

Animals↗
PubMed2026

Genome-wide CRISPRi screen in human iNeurons identifies novel negative mTOR regulator genes associated with focal cortical dysplasia.

Focal cortical dysplasia (FCD) is a common cause of focal epilepsy that typically results from brain mosaic mutations in the mTOR cell signaling pathway. To identify new potential FCD genes, we developed an in vitro CRISPRi screen in human neurons and used FACS enrichment based on the FCD biomarker, phosphorylated S6 ribosomal protein (pS6). Using whole-genome (110,000 gRNAs) and candidate (129 gRNAs) libraries, we discovered 6 new genes in which loss of function significantly increases pS6 levels: LRRC4, EIF3A, TSN, HIP1, PIK3R3, and URI1. Further analysis of the mTOR pathway showed that only two of the genes, PIK3R3 and HIP1, caused hyperphosphorylation throughout the AKT/mTOR/S6 signaling pathway. Importantly, potential pathogenic variants in these two genes have been reported in resected brain tissue from a single FCD patient each, supporting the predictive validity of our screen. Knocking down each of the 6 genes in iNeurons made mTOR signaling resistant to the loss of neurotrophic factor signaling, specifically GDNF; even without GDNF, pS6 levels remained comparable to GDNF-stimulated controls. Thus, we have identified negative regulators of neuronal mTOR signaling in the context of lost neurotrophic factor support. Our data expand the set of genes that are likely to regulate mTOR pathway signaling in neurons, provide biological confirmation for candidate genes identified in human tissue, and suggest additional targets for investigating somatic gene variants in resected FCD tissues. The identification of novel mTOR regulators using iNeurons also highlights the importance of genetic screening in disease-related cell types.

Brain mosaicism↗
PubMed1985

Studies on rat mammary adenocarcinomas: a model for metastasis.

Studies carried out by the authors on the rat mammary adenocarcinoma cell lines MAT 13762 and DMBA-8 are summarized. A series of variants and somatic cell hybrids have been prepared and partially characterized in terms of phenotypic properties which may correlate with metastatic potential. These include measurement of in vitro migration, lectin binding properties, expression of procoagulant activity and shedding of cell surface components. Particular emphasis has been placed on the production of enzymically-active plasminogen activator, as this seems to correlate with the ability of cells to metastasize. The finding has also been made that several of the cell types studied produce, in vitro, an inhibitor of plasminogen activator which may influence the metastatic behaviour of tumor cells. Results obtained are discussed in the context of the usefulness of these tumor systems for the study of spontaneous and experimental metastasis and the factors involved in these processes. Preliminary results of cloning and fluctuation analysis of metastatic potential together with discussion of the role of the metastatic heterogeneity and the formation of metastatic variants by mutation events are included.

Adenocarcinoma↗
PubMed1990

Failure of cell surface expression of a class I major histocompatibility antigen caused by somatic point mutation.

The ability to down-regulate major histocompatibility complex class I antigen expression on allografts prior to transplantation would be expected to improve their survival in immunocompetent recipients. In order to identify genetic mechanisms that mediate attenuation of MHC class I antigen expression, we have begun characterizing H-2Kb surface null somatic cell variants derived from an H-2 heterozygous tumor cell line (H-2b X H-2d). These variants have sustained a modification in cell surface MHC phenotype, as evidenced by their failure to be recognized by both anti-H-2Kb antibodies and cytotoxic T lymphocytes. The mutant phenotype for one such variant (designated 69.9.15) was marked by the expression of abundant H-2Kb mRNA and immuno-precipitable H-2Kb protein in cell lysates. The failure in cell surface expression of the H-2Kb antigen was caused by a single base change (G to A transition) in exon 3, encoding the second external domain (alpha 2) of the H-2Kb molecule. The mutation resulted in the substitution of Tyr for Cys at amino acid position 164, thereby disrupting an intrachain disulfide linkage formed between Cys 101 and 164. In contrast to the wild-type H-2Kb gene, DNA-mediated transfer of the mutant H-2Kb gene into mouse L cell fibroblasts failed to result in cell surface expression of the H-2Kb antigen, although both the wild-type and mutant genes were transcribed to equivalent levels. These data indicate that a genetic event as limited as somatic point mutation can abrogate expression of a MHC class I antigen and provide support for the hypothesis that protein folding plays an important role in the cell surface expression of MHC class I molecules.

Animals↗
PubMed2026

Medically Unexplained Symptoms: A Systematic Umbrella Review of Current Terminology and Reported Rationales.

OBJECTIVES: Toaddress current naming conventions for Medically Unexplained Symptoms (MUS) through a systematic umbrella review. The terminology used and the provided rationales were considered. METHODS: Registered with PROSPERO (CRD42024526020), this review searched 8 key databases, last on January 28, 2025. Reviews including medically unexplained symptoms (or synonym or subtype) in their systematic search terms were included (N=422). RESULTS: A total of 577 references to 111 terms were made across the reviews, with numerous reviews using the same overarching terms, including "functional" (n=233), "somatic" (or variants thereof, n=51), and "medically unexplained" (n=28). Thirty percent of terms (n=179) were to specific syndromes or terms that did not group together under an overarching term, suggesting substantial variability in terms, even though over 60% of authors were primarily associated with just 3 disciplines: medicine, allied health, and psychology. A subset of 23 reviews provided rationales, which were subjected to content analysis and a ROBIS (Risk of Bias in Systematic Reviews) risk-of-bias assessment. This analysis showed that rationales tended to (1) highlight differences between psychological, psychiatric, and other medical fields (n=7); (2) focus on the patient perspective and patient-practitioner therapeutic relationship (n=10); or (3) follow broad and/or commonly used terms (n=7). DISCUSSION: The current landscape of terminology used for MUS remains varied, nuanced, and inconsistent between disciplines. Moving forward to a more universal language accepted and used by both patients and practitioners would aid in the diagnosis, management, and treatment of MUS.

Humans↗
PubMed1991

Defective assembly of class I major histocompatibility complex molecules in an embryonic cell line.

Developmentally regulated expression of the products of the major histocompatibility complex (MHC) is thought to play a key role in maternal tolerance of the fetal allograft. Here we analyze a cell line (EE2H3), derived from early post-implantation-stage mouse embryos, that is defective for MHC class I assembly. To follow expression of a single well-defined class I product, we introduced the H-2Dd gene under control of the human beta-actin promoter. We found that the transfected EE2H3 cells expressed abundant levels of H-2Dd heavy chains and beta 2-microglobulin protein, but only small amounts of H-2Dd surface protein. Surface expression was rescued by the addition of an appropriate antigenic peptide, or by culturing the cells at low temperature. The phenotype exhibited by EE2H3 is thus remarkably similar to that described for class I-negative somatic cell variants selected using antibodies and complement. However, a striking difference was that surface expression in H-2Dd-transfected EE2H3 cells was markedly enhanced in response to treatment with interferon. Thus, we have identified a novel class I assembly-defective cell line. Considering that EE2H3 was established from primary cultures of mouse embryo cells without immunoselection, and is therefore likely to represent a cell population normally present in post-implantation-stage embryos, these findings raise the possibility that expression of class I surface antigens during early development may in part be controlled post-translationally at the level of MHC class I assembly.

Animals↗
PubMed1995

Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas.

The gene encoding the cell-cycle regulatory protein p16, CDKN2, is localized on chromosome band 9p21. CDKN2 is frequently deleted or mutated in a variety of tumor cell lines, including pancreatic cancer cell lines and xenografts, as well as in some primary tumors. We examined 32 primary pancreatic adenocarcinomas for CDKN2 mutations and for loss of heterozygosity of 9p21 sequences to assess the role of CDKN2 in pancreatic carcinogenesis. Single-strand conformation variant analysis (SSCV) and direct sequencing of the variants revealed somatic CDKN2 mutations in 11 of 32 tumors (five frame-shift mutations, five nonsense mutations, and one missense mutation). One tumor appeared to be characterized by homozygous deletion of CDKN2. These results suggest that CDKN2 plays an important role during tumorigenesis or tumor progression in a significant proportion of pancreatic adenocarcinomas.

Adenocarcinoma↗
PubMed1985

Genetic complementation in somatic cell hybrids of four variants of infantile GM2 gangliosidosis.

Cell hybridizations between fibroblasts of four variants (B, O, AB, and B1) of infantile GM2 gangliosidosis were performed. Cocultivated as well as hybrid cells were analyzed for their capability to degrade exogenously added [3H]-GM2. Hybridization of variant AB fibroblasts with fibroblasts of variant O, variant B, or variant B1 resulted in an enhanced rate of GM2 hydrolysis, showing intergenic complementation. Similar restoration of GM2 catabolism was observed after hybridization of variant B1 cells with variant O, but not with variant B cells. These results indicate that B1 cells carry a mutation in the gene locus for the alpha-subunit of beta-hexosaminidase. Studies of the processing of immature enzyme in variant B1 cells showed the presence of alpha-precursors and mature alpha-chains, but at a lower level as compared to normal cells.

Electrophoresis, Polyacrylamide Gel↗