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At least 577 records · Page 32Linked to original sources
PubMed1996

Evidence of somatic mutations in osteoarthritis.

We examined, cytogenetically and by in situ hybridization (ISH) techniques, the synovia, osteophytes, and articular cartilage from 32 patients with pronounced osteoarthritis (OA), a prevalent form of arthropathy characterized by progressive reduction of articular cartilage, and synovial samples from 17 control patients. In short-term cultures, clonal chromosome aberrations, in particular the gain of chromosomes 7 (+7) and 5 (+5), were found to be strongly associated with OA. These aberrations were found in almost 90% of the cultures from synovia and osteophytes, whereas only 1/11 synovial samples from joints unequivocally unaffected by OA had cells with +5 or +7. The in vivo nature of trisomy 7 was demonstrated by ISH on uncultured cells, and serial passaging showed that cells with +7 had a proliferative advantage in vitro. Thus, the combined data indicate that cells with somatic mutations appear early and may be influential in the disease process leading to OA.

Adult↗
PubMed1996

Monoclonal immunoglobulin A derived from peritoneal B cells is encoded by both germ line and somatically mutated VH genes and is reactive with commensal bacteria.

We transferred peritoneal cells from BALB/c mice into C.B17 scid/scid mice. Six to eight months after injection, only cells with the B1 phenotype were retained in the spleens and peritoneal cavities of these mice. The lamina propria of the intestine contained many peritoneal, donor-derived, immunoglobulin A (IgA)-producing cells. The mesenteric lymph nodes of these mice were found to be a major site of proliferation and generation of IgA plasmablasts. We established eight IgA-producing hybridomas from the mesenteric lymph nodes of such mice, and all the hybridomas reacted with different but partially overlapping fecal bacterial populations. Cloning and sequencing of the VH genes of these hybridomas showed that two hybridomas utilized germ line-encoded VH genes while the VH genes of the six hybridomas showed somatic mutations, some of which are indicative of an antigen-driven selection process.

Animals↗
PubMed2005

Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer.

Cancer often results from the accumulation of multiple genetic alterations. Although most malignancies are sporadic, only a small number of genes have been shown to undergo frequent mutations in sporadic cancers. The long arm of chromosome 16 is frequently deleted in human cancers, but the target gene for this deletion has not been identified. Here we report that ATBF1, which encodes a transcription factor that negatively regulates AFP and MYB but transactivates CDKN1A, is a good candidate for the 16q22 tumor-suppressor gene. We narrowed the region of deletion at 16q22 to 861 kb containing ATBF1. ATBF1 mRNA was abundant in normal prostates but more scarce in approximately half of prostate cancers tested. In 24 of 66 (36%) cancers examined, we identified 22 unique somatic mutations, many of which impair ATBF1 function. Furthermore, ATBF1 inhibited cell proliferation. Hence, loss of ATBF1 is one mechanism that defines the absence of growth control in prostate cancer.

Cell Proliferation↗
PubMed1987

Somatically mutated forms of a major anti-p-azophenylarsonate antibody variable region with drastically reduced affinity for p-azophenylarsonate. By-products of an antigen-driven immune response?

The pivotal role played by antigen in the clonal selection of B cells for initial participation in an immune response is well established. Antigen selective mechanisms ensure that antigen-binding antibodies are produced during all stages of the immune response. However, antibodies that lack specificity for the immunogen might also be produced during the course of an antigen-driven immune response . It has been suggested that, through idiotype-antiidiotype network interactions within the immune system, production of antibodies that lack specificity for the immunogen but that share idiotopes with antigen-binding antibodies could result (1). In addition, data obtained by a number of investigators suggest that somatic mutation of antibody V region genes occurs at a rate of 10(-3)/basepair/cell division in B cells participating in an immune response (2, 3). One outcome of such V region structural alteration could be antibodies that lack, or have drastically reduced affinity for the immunogen . We sought to identify and characterize some of the antibody by-products of the antigen-driven immune response that are expected to be created by the mechanisms described above.

Amino Acid Sequence↗
PubMed1997

Hereditary nonpolyposis colorectal cancer: causative role of a germline missense mutation in the hMLH1 gene confirmed by the independent occurrence of the same somatic mutation in tumour tissue.

Evaluation of the causative role of germline mutations in DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) families can be difficult. Whereas nonsense, frameshift or splice-site mutations are presumed to lead to dysfunctional gene products and thus are generally considered to be causative, the evaluation of missense mutations often remains uncertain. We observed a novel germline mutation in the hMLH1 gene (His-->Pro at codon 329) in an HNPCC family. The same missense mutation also occurred as a somatic event in the colonic tumours of two other HNPCC patients who had germline mutations at different sites of the hMLH1 gene. Thus, the H329P mutation present in the germline can be considered as having an aetiological role in this HNPCC family.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Overexpression of a Rrp1 transgene reduces the somatic mutation and recombination frequency induced by oxidative DNA damage in Drosophila melanogaster.

Recombination repair protein 1 (Rrp1) includes a C-terminal region homologous to several DNA repair proteins, including Escherichia coli exonuclease III and human APE, that repair oxidative and alkylation damage to DNA. The nuclease activities of Rrp1 include apurinic/apyrimidinic endonuclease, 3'-phosphodiesterase, 3'-phosphatase, and 3'-exonuclease. As shown previously, the C-terminal nuclease region of Rrp1 is sufficient to repair oxidative- and alkylation-induced DNA damage in repair-deficient E. coli mutants. DNA strand-transfer and single-stranded DNA renaturation activities are associated with the unique N-terminal region of Rrp1, which suggests possible additional functions that include recombinational repair or homologous recombination. By using the Drosophila w/w+ mosaic eye system, which detects loss of heterozygosity as changes in eye pigmentation, somatic mutation and recombination frequencies were determined in transgenic flies overexpressing wild-type Rrp1 protein from a heat-shock-inducible transgene. A large decrease in mosaic clone frequency is observed when Rrp1 overexpression precedes treatment with gamma-rays, bleomycin, or paraquat. In contrast, Rrp1 overexpression does not alter the spot frequency after treatment with the alkylating agents methyl methanesulfonate or methyl nitrosourea. A reduction in mosaic clone frequency depends on the expression of the Rrp1 transgene and on the nature of the induced DNA damage. These data suggest a lesion-specific involvement of Rrp1 in the repair of oxidative DNA damage.

Alkylating Agents↗
PubMed1987

Constitutive functional heterogeneity without detectable somatic mutation of antigen receptor genes in helper T cell clones: possible regulation by novel HLA class II "DY" determinants.

The majority of interleukin 2-dependent HLA class II alloreactive human CD4-positive helper T-cell clones (TCC) presented the phenomenon of constitutive intraclonal heterogeneity, as reflected by limiting dilution analysis of changing frequencies of autonomously proliferative cells within the monoclonal population. Moreover, at 30-35 population doublings, these TCC lost their allospecific proliferative and helper capacity (phase I) and instead acquired strong antigen-non-specific suppressive activity (phase II). The TCR was still expressed at the same level on the cell surface. As shown by stable and identical rearrangement profiles of their T-cell receptor beta- and gamma-chain genes in both phases I and II, this constitutive change of function was probably not due to somatic mutation of the genes coding for the antigen-specific receptor. Moreover, antigen specific reactivity was retained in phase II TCC by the criterion of specifically stimulated secretion of granulocyte/macrophage colony stimulating factor. The preprogrammed intra-clonal functional flexibility is explained here by invoking a novel regulatory mechanism mediated by a fourth group of HLA class II determinants. When TCC were used as stimulators with the appropriate primed responders, it could be demonstrated that phase I autonomously proliferative non-suppressive T-helper lines failed to express certain novel lymphocyte activating determinants (LADs), whereas after their acquisition of suppressive function (phase II) these LADs were present. These stimulatory moieties appeared to represent a novel class II-like structure as established by serology, immunochemistry and functional characterization employing monoclonal antibodies to block stimulation. These operationally designated "DY" determinants are primarily and thus far exclusively involved in the induction of antigen non-specific suppressor cells. It is proposed that the intra-clonal changes of T-cell function described here are mediated by a switch in the utilization of qualitatively distinct class II-like restriction elements. The functional status of the phase I TCC can be altered by a switching over to the engagement of "DY" determinants in phase II. Thus, an autostimulatory and self-maintaining suppressive network may operate in extended inductive phases of human HLA restricted T-cell responses.

Cell Membrane↗
PubMed1996

Gene family use and somatic mutation in primary and secondary fluorescein-specific IgM antibody responses.

A comparative analysis of the DNA sequences of primary and secondary IgM, fluorescein-specific antibodies was performed. These antibodies were secreted by hybridomas generated following fusion of immunized BALB/c mouse lymphocytes and SP2/0 myeloma cells. Our results show that primary and secondary fluorescein-specific IgM antibodies use a variety of segments from the variable region of the immunoglobulin heavy chain locus (VH), with members of the J558 and 7183 VH gene families predominating in both populations. D regions from the DF116 and DSP2 families were used exclusively in our primary antibody sample and predominated in the secondary response. In the primary antibodies, 15 out of 18 definable D regions were transcribed in reading frame one, but in the secondary antibodies the three reading frames were used stochastically. Secondary IgM antibodies showed a higher frequency of somatic mutation than their primary counterparts, but we could detect no evidence of selection for mutations in the complementarity determining regions as compared with the framework regions. It appears that fusion of secondary cells, 3-6 days after immunization, is able to 'capture' the IgM-producing population of B cells at a stage in their development following mutation but prior to antigenic selection.

Amino Acid Sequence↗
PubMed1999

Accelerated accumulation of somatic mutations in mice deficient in the nucleotide excision repair gene XPA.

Inheritable mutations in nucleotide excision repair (NER) genes cause cancer-prone human disorders, such as xeroderma pigmentosum, which are also characterized by symptoms of accelerated ageing. To study the impact of NER deficiency on mutation accumulation in vivo, mutant frequencies have been determined in liver and brain of 2-16 month old NER deficient XPA-/-, lacZ hybrid mice. While mutant frequencies in liver of 2-month old XPA-/-, lacZ mice were comparable to XPA+/-, lacZ and the lacZ parental strain animals, by 4 months of age mutant frequencies in the XPA-deficient mice were significantly increased by a factor of two and increased further until the age of 16 months. In brain, mutant frequencies were not found to increase with age. These results show that a deficiency in the NER gene XPA causes an accelerated accumulation of somatic mutations in liver but not in brain. This is in keeping with a higher incidence of spontaneous liver tumors reported earlier for XPA-/- mice after about 15 months of age.

Age Factors↗
PubMed1984

Activation and somatic mutation of the translocated c-myc gene in burkitt lymphoma cells.

In contrast to other human tumors in which the c-myc gene and its transcript are greatly amplified, careful analysis of t(8;14) Burkitt cell lines indicates that the c-myc transcript is marginally, and in some cases not at all, increased by comparison to control lymphoblastoid cell lines. Instead, there is a more subtle alteration in the expression of the translocated c-myc gene characterized by a shift in promoter utilization and an apparent insensitivity to the regulation that inactivates the normal c-myc allele within these same cells. In some Burkitt cell lines, such deregulation might be because of the loss of a putative control region through removal of the large dual promoter/leader segment of the c-myc gene. In other cell lines, however, this deregulation may be explained by somatic mutations that occur within the putative control region even though it is located many hundreds of bases from the translocation breakpoint.

Alleles↗
PubMed1986

Somatic mutations at a heterozygous autosomal locus in human cells occur more frequently by allele loss than by intragenic structural alterations.

A human B-cell lymphoblastoid cell line heterozygous at the thymidine kinase (TK) locus (i.e., carrying one functional and one nonfunctional thymidine kinase allele) was used to study the molecular nature of mutations leading to loss of TK activity. A total of 113 mutant clones, both spontaneous and induced, were examined by restriction enzyme mapping and by the use of a restriction fragment length polymorphism (RFLP) at the TK locus. A majority (71%) of all mutant clones examined had lost the entire functional TK allele, becoming either homozygous or hemizygous for the nonfunctional allele. The remaining mutants had either no detectable changes (26%) or had obvious structural alterations (less than 5%) in the active TK gene. These results emphasize the importance of allele loss, presumably by mitotic chromosomal mechanisms, in mutagenesis at autosomal loci, and suggest that in vitro models for recessive somatic mutation which are based at hemizygous loci may ignore a large category of genetically significant events.

B-Lymphocytes↗
PubMed1987

Clustered somatic mutations in and around first exon of non-rearranged c-myc in Burkitt lymphoma with t(8;22) translocation.

We have examined the restriction map of the c-myc gene in 15 BL cell lines carrying the variant t(8;22) translocation in which c-myc is known to remain on chromosome 8. Using 3 restriction enzymes cutting outside the c-myc domain (EcoRI, BamHI, HindIII), we found no evidence for a c-myc/Ig lambda rearrangement in 14 BL cell lines. In the last one, BL 37, the 3' flanking region was rearranged corresponding to the already identified breakpoint located 400 pb downstream from the c-myc gene (9). Using 4 restriction enzymes cutting inside the c-myc gene (PvuII, PstI, SacI, HincII) we looked for discrete abnormalities within the gene limits, and we found in 9 BL cell lines several abolished and created sites, compatible with multiple independent somatic mutations. They are significantly clustered in the 5' non coding region, with a striking prevalence at the end of exon 1. The role of mutations in the non-coding first exon region for the deregulation of c-myc expression is discussed.

Burkitt Lymphoma↗
PubMed2001

Primary central nervous system lymphomas express Vh genes with intermediate to high somatic mutations.

Primary central nervous system lymphoma (PCNSL) is a rare disease, especially among non-AIDS patients. Although almost all PCNSLs belong to the diffuse large B-cell lymphoma (DLBL) category, its clinical course differs from that of other types of DLBL. To elucidate the histogenesis of PCNSL, we analyzed the source of the cells from its variable region (VH) sequences using the polymerase chain reaction (PCR) method to amplify the immunoglobulin heavy chain (IgH) gene of DNA extracted from paraffin sections. Fifteen patients with AIDS-unrelated PCNSL of DLBL type, (7 males and 8 females), were evaluated. Only one case showed positive evidence of EBV infection. The prognosis was very poor with a median survival of 9 months. Analysis of the VH sequences revealed that the VH4 family was used in 4 cases and the VH3 family in 2 cases. The homology with previously published germline sequences was random, ranging from 82.7-93.2%, showing intermediate to high somatic mutations. In 3 of 6 cases, the existence of intraclonal diversity was suspected. These findings suggest that PCNSLs are histogenetically derived from antigen selected B cells in the germinal center (GC) environment.

Adult↗
PubMed2002

Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation.

Although idiopathic thrombocytopenic purpura (ITP) is the most common autoimmune hematologic disorder, little is known about the associated autoantibodies on a molecular level. Consequently, diagnostic assays and therapy for ITP lack specificity. To avoid technical limitations imposed by B-cell immortalization methods, we used repertoire cloning (Fab/phage display) to clone platelet autoantibodies and examine the relation between immunoglobulin (Ig) gene usage, clonality, and antigen specificity. Phage display libraries were constructed from splenocytes from 2 patients with chronic ITP, and competitive cell-surface selection was used to isolate several dozen unique IgG platelet-specific autoantibodies. Platelet-reactive Fabs in both patients were associated almost exclusively with rearrangements of a single Ig heavy-chain variable-region gene (V(H)3-30), despite an apparent diversity of antigen specificities. Comparative analysis of platelet-reactive Fab Ig gene rearrangements from each patient suggested that they evolved from a restricted number of B-cell clones through somatic mutation with high replacement-to-silent mutation ratios. Although V(H)3-30-encoded heavy chains were found with light chains encoded by several different Ig genes, molecular repairing experiments showed exquisite restriction on the specific heavy- and light-chain pairings that permitted platelet reactivity. Together, these data suggest that the development of platelet-reactive antibodies associated with ITP is driven by an encounter with diverse platelet antigens through the clonal expansion of B cells using genetically restricted and highly specific combinations of heavy- and light-chain gene products. The extraordinarily high usage of the V(H)3-30 heavy-chain gene in these patients has implications for the pathogenesis, diagnosis, and management of chronic ITP.

Adult↗
PubMed1999

Somatic mutations at the SRD5A2 locus encoding prostatic steroid 5alpha-reductase during prostate cancer progression.

Prostate cancer is a serious public health problem in many industrialized countries. Androgens appear to play a critical role in its etiology. Specifically, the active androgen in the prostate, dihydrotestosterone (DHT) which is synthesized by the enzyme steroid 5alpha-reductase from testosterone (T), acts as a mitogen. Hence androgen-deprivation is commonly used during prostate cancer therapy. Two isozymes for steroid 5alpha-reductase have been reported. The type II enzyme is prostate-specific and encoded by the SRD5A2 gene. We have investigated a polymorphic (TA)n dinucleotide repeat in the 3' UTR (untranslated region) of the SRD5A2 gene in 30 matched samples of constitutional ("germline") DNA from peripheral blood lymphocytes and microdissected, pure tumor DNA. We report here 8 LOH (loss of heterozygosity) events and 9 cases of microsatellite instability at this marker. Therefore, almost 57% of the samples examined showed evidence of somatic mutations at the 3' UTR of the SRD5A2 locus. Our data suggest that the SRD5A2 gene may be involved in prostate cancer progression and that this may have relevance for treatment of the disease.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1998

Clonally related IgE and IgG4 transcripts in blood lymphocytes of patients with asthma reveal differing patterns of somatic mutation.

Isotype switching to IgE contributes to atopic asthma, therefore strategies to divert this process to alternative isotypes could have therapeutic relevance. It is known that patients with allergic disease have serum IgE and IgG4 antibodies with similar specificities, and that cytokines such as IL-4 mediate switching to both of these isotypes. Availability of variable region gene analysis has allowed us to probe isotype variants at the single-cell level. An earlier report described identification in a single atopic patient of short transcripts with a common complementarity-determining region "clonal signature" in combination with C mu, C gamma4 and C epsilon. We have extended this analysis, and have identified V(H)-Cgamma4 transcripts with clear clonal relationship to IgE-derived sequences in blood lymphocytes from three of four patients with atopic asthma. No other IgG subclasses were detected, confirming the link between IgE and IgG4. Full sequences were obtained from each clonally related isotype in all patients, and showed extensive somatic mutation. As previously found for IgE, the IgG4 isotypes had evident intraclonal variation. There were shared mutations between isotypes, but also many differences, indicative of separate cell populations with divergent mutational histories. These findings indicate that, in atopic patients, an individual B cell commonly switches to either IgE or IgG4. Cells producing each isotype then co-exist in the recirculating pool, and the balance between them may influence the disease process.

Amino Acid Sequence↗
PubMed1988

Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma.

The most common translocation in human lymphoma, the t(14;18)(q32;q21), generates heterogeneous 4.2-7.2 kb Bcl-2-immunoglobulin (Ig) chimeric mRNAs resulting from alternative Bcl-2 5' exons and varied Ig 3' untranslated regions (UT). The normal human Bcl-2 gene has a three exon structure with an untranslated first exon, a facultative 220 bp intron I, but an enormous 370 kb intron II. S1 protection and primer extension analysis defined initiation sites in exon II associated with classic promoter elements and a decanucleotide (ATG-CAAAGCA) homologous with Ig variable region enhancers. Multiple initiation sites were also found in a GC-rich region with Sp1 binding motifs in exon I. Most t(14;18) breakpoints cluster within the 3' UT of Bcl-2 implicating that event in gene deregulation. The Bcl-2 gene introduced into the Ig constant (C gamma) locus of SU-DHL-6 displayed somatic mutation. While Bcl-2--Ig mRNAs demonstrated an unaltered 2.5 h half-life, the Bcl-2--Ig gene revealed an inappropriately high rate of transcription for a mature B-cell. This indicates the translocated Bcl-2 allele has escaped normal control mechanisms.

Amino Acid Sequence↗
PubMed1992

Lupus anti-DNA antibodies bearing the 8.12 idiotype appear to be somatically mutated.

Anti-DNA antibodies in systemic lupus erythematosus (SLE) sera were analyzed using an antiidiotype designated 8.12 which recognizes a determinant on lambda light chains highly expressed in SLE sera. Eight of ten normal individuals had peripheral blood lymphocytes which produced high-titered 8.12-positive antibodies, following transformation with Epstein Barr virus, implying that the 8.12-reactive sequence originates in the germline gene (GLG). Of 58 SLE sera, 32 contained elevated titers of 8.12-reactive antibodies. Twenty-three of these sera had 8.12-reactive anti-DNA antibodies, suggesting a strong correlation between 8.12 idiotype and DNA binding. Moreover, 20 of 26 8.12-reactive IgG antibodies and only 4 of 10 8.12-reactive IgM antibodies bound DNA (P less than 0.05). These observations strengthen our previous findings in myeloma sera that DNA binding is associated with IgG isotype in the 8.12 idiotype system and suggest that the acquisition of anti-DNA reactivity in antibodies bearing the GLG idiotype 8.12 is achieved by somatic mutation, a feature of an antigen-driven response.

Antibodies, Antinuclear↗