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PubMed2003

Extrasalivary lymphoma development in Sjögren's syndrome: clonal evolution from parotid gland lymphoproliferation and role of local triggering.

OBJECTIVE: To characterize Sjögren's syndrome (SS)-related B cell lymphoproliferation at the premalignant stage and during the evolution to B cell lymphoma, and to better understand the pathobiologic mechanisms associated with clonal expansion and the possible influence of different microenvironments on neoplastic transformation. METHODS: We analyzed sequential parotid and lung biopsy specimens that were obtained from a single patient with SS at multiple time points over a 7-year period. Polymerase chain reaction DNA amplification, cloning, and sequencing of the immunoglobulin heavy chain variable region showed clonality, somatic mutations, intraclonal heterogeneity, and genealogic relationships of the B cell clones in the different biopsy specimens. RESULTS: The evolution of a nonmalignant B cell clone that was present in the parotid gland and evolved into a B cell lymphoma was documented. During such a process, one subclone was selected that accumulated somatic mutations in a pattern consistent with the preservation of antigen receptor functionality, possibly attributable to continued hypermutation and selection. Intraclonal diversity indicated the presence of local triggers in both the parotid and lung microenvironments. CONCLUSION: Molecular followup of B cell lymphoproliferation in SS, from nonmalignant stage to overt B cell lymphoma, indicated a role for B cell receptor engagement in clonal survival. The outgrowth of one subclone, with malignant transformation in the lung, a target organ different from the initial site of the lymphoproliferative process (the parotid gland), indicates that resident stimuli in different microenvironments may locally sustain ongoing lymphoproliferation and B cell transformation.

Adult↗
PubMed1999

Spontaneous deleterious mutation in Arabidopsis thaliana.

The frequency and selective impact of deleterious mutations are fundamental parameters in evolutionary theory, yet they have not been directly measured in a plant species. To estimate these quantities, we allowed spontaneous mutations to accumulate for 10 generations in 1,000 inbred lines of the annual, self-fertilizing plant Arabidopsis thaliana and assayed fitness differences between generations 0 and 10 in a common garden. Germination rate, fruit set, and number of seeds per fruit each declined by less than 1% per generation in the mutation lines, and total fitness declined by 0.9% per generation. Among-line variances increased in the mutation lines for all traits. Application of an equal-effects model suggests a downwardly biased genomic deleterious mutation rate of 0.1 and a upwardly biased effect of individual mutations on total fitness of 20%. This genomic deleterious mutation rate is consistent with estimates of nucleotide substitution rates in flowering plants, the genome size of Arabidopsis, and the equilibrium inbreeding depression observed in this highly selfing plant species.

Arabidopsis↗
PubMed2003

A systematic analysis of sequences of human antiphospholipid and anti-beta2-glycoprotein I antibodies: the importance of somatic mutations and certain sequence motifs.

OBJECTIVE: Previous studies have suggested the importance of somatic mutations and certain residues in the complementarity determining regions (CDRs) of antiphospholipid antibodies (aPL) implicated in the pathogenesis of antiphospholipid antibody syndrome (APS). The authors tested this hypothesis by carrying out a systematic analysis of all published aPL sequences. METHODS: Each aPL variable region sequence was aligned to the closest germline counterpart in the VBASE Sequence Directory by using DNAPLOT software, allowing analysis of nucleotide homology and distribution of somatic mutations. The probability that this distribution arose as a result of antigen-driven accumulation of replacement mutations in the CDRs was tested statistically. RESULTS: There was no preferential gene or family use in the 36 aPL sequences identified. Immunoglobulin (Ig) M aPL had few somatic mutations compared with IgG. Of the IgG aPL, 9 of 14 showed evidence of antigen-driven accumulation of replacement mutations in the CDRs. Multinomial analysis allowed a clearer statistical identification of sequences that had been subject to antigen drive. The more specific IgM aPL and some IgG aPL displayed an accumulation of arginine, asparagine, and lysine residues in CDRs. CONCLUSIONS: High-specificity binding in IgG aPL, but not in more specific IgM aPL, is conferred by antigen-driven somatic mutation. This may in part be caused by an accumulation of arginine, asparagine, and lysine residues in the CDRs, which are germlines encoded in the more specific IgM aPL, but often arise because of somatic mutation in IgG aPL. RELEVANCE: An understanding of the role of arginine, asparagine, and lysine residues in the binding of pathogenic aPL to phospholipids, and to beta(2)-glycoprotein I, may eventually help in the development of drugs to interfere with those interactions, and thereby improve the treatment of antiphospholipid antibody syndrome.

Amino Acid Sequence↗
PubMed1994

Increased frequency of mutations in the hprt gene of T cells isolated from patients with anti-U1-70kD-autoantibody-positive connective tissue disease.

Mixed connective tissue disease (MCTD) is characterized by the presence of high titers of anti-U1-70kD autoantibodies which are the result of substantial B cell activation. The hprt gene encodes the constitutively expressed enzyme hypoxanthine-guanine phosphoribosyl transferase which is active in the purine salvage pathway. Rapidly dividing cells randomly accumulate gene mutations, including mutations in the hprt gene. These mutations may be used to identify activated cells. If activated T cells play a role in the pathogenesis of MCTD, an increased frequency of mutations in the hprt gene might be expected among T cells isolated from such patients. To examine this hypothesis, we isolated and cloned T cells from 10 anti-U1-70kD-autoantibody-positive MCTD patients and determined the precursor frequencies of cells possessing mutations in hprt by comparing the frequency of cells grown in the presence and absence of the purine analogue 6-thioguanine. We found that the frequency of 6-thioguanine-resistant hprt-negative T cells was significantly increased among MCTD patients (mean 566/10(6); range 122-2,845/10(6)) versus age- and sex-matched controls (mean 42/10(6); range 21-78/10(6); p < 0.003). These results demonstrate that there is an increase in the measured mutant frequency of T cells from MCTD patients. Such T cells may play a role in the pathogenesis of this disease.

Adult↗
PubMed2006

The FEATHERED gene is required for polarity establishment in lateral organs especially flowers of the Japanese morning glory (I pomoea nil ).

Most strains harboring the feathered (fe) mutation in the Japanese morning glory (Ipomoea nil or Pharbitis nil) show deformed phenotypes such as upcurled leaves and separated or tubular petals. These phenotypes seem to be caused by loss of abaxial identity in lateral organs. The FE gene was isolated using the inserted transposon as a tag. An En/Spm-related transposable element, Tpn102, inserted in the fourth intron of the FE gene, was responsible for the fe mutation. FE encodes a GARP transcription factor closely related to Arabidopsis KANADI1 (KAN1), which promotes an abaxial cell fate. Genetic analyses and molecular studies, which showed that all fe mutant strains have the same fe allele despite their phenotypic differences, revealed that fe strains with strong phenotypes have additional mutations enhancing the fe phenotype. These findings and historical records of fe phenotypes suggest that these enhancer mutations were accumulated in the fe background during selection for strong phenotypes. The mutant phenotypes and molecular analysis of fe strains suggest that FE regulates the abaxial identity of lateral organs redundantly with modifier genes, as KAN1 does in Arabidopsis. FE, however, affects flower phenotype even in the single mutant unlike KAN1, moreover, modifier mutations affect flower phenotype only in the fe mutant background, suggesting that FE may play a more crucial role in promotion of abaxial cell fate in flowers of the Japanese morning glory.

Amino Acid Sequence↗
PubMed2006

Dynamics of mutation and recombination in a replicating population of complementing, defective viral genomes.

In a previous study, we documented that serial passage of a biological clone of foot-and-mouth disease virus (FMDV) at high multiplicity of infection (moi) in cell culture resulted in viral populations dominated by defective genomes that included internal in-frame deletions, affecting the L and capsid-coding regions, and were infectious by complementation. In the present study, analyses of the defective genomes present in individual viral plaques, and of consensus nucleotide sequences determined for the entire genomes of sequential samples, have revealed a continuous dynamics of mutation and recombination. At some points of high genetic instability, multiple minority genomes with different internal deletions co-existed in the population. At later passages, a new defective RNA arose and displaced a related, previously dominant RNA. Nucleotide sequences of the different genomic forms found in sequential isolates have revealed an accumulation of mutations at an average rate of 0.12 substitutions per genome per passage. At the regions around the deletion sites, substantial, minor or no nucleotide sequence identity is found, suggesting relaxed sequence requirements for the occurrence of internal deletions. Competition experiments indicate a selective advantage of late phase defective genomes over their precursor forms. The defective genome-based FMDV retained an expansion of host cell tropism, undergone by the standard virus at a previous stage of the same evolutionary lineage. Thus, despite a complex dynamics of mutation and recombination, and phases of high genetic instability, a biologically relevant phenotypic trait was stably maintained after the evolutionary transition towards a primitive genome segmentation. The results extend the concept of a complex spectrum of mutant genomes to a complex spectrum of defective genomes in some evolutionary transitions of RNA viruses.

Animals↗
PubMed1992

Somatic mutation during metastasis of a mouse fibrosarcoma line detected by DNA fingerprint analysis.

Metastatic nodules were examined by DNA fingerprint analysis. The probes used, Pc-1 and Pc-2, detect mutations as shifts in bands of the minisatellite loci which are dispersed among chromosomes. Four clonal lines of a fibrosarcoma from an F1 mouse (C57BL/Ka x C3H/He) were selected for various metastatic potentials upon inoculation into syngeneic mice. These four lines exhibited many extra bands resulting from recombination and/or DNA slippage, indicating accumulation of mutations during the successive passages in mice. One of the four, a 505 cell line which had been passaged extensively in vitro and consisted of a heterogenous population, was inoculated into thirteen syngeneic mice, and gave rise to six lung metastatic nodules in two mice. All the nodules showed band-patterns distinct from one another, although nodules within a given mouse tended to show similar patterns. When a genetically tagged 505-05-01 clone was analyzed, three of nine metastatic nodules obtained also revealed new bands. These results strongly suggest that somatic mutations occur at a high frequency during metastasis, providing direct evidence of genetic instability of the tumor cells.

Animals↗
PubMed1993

Spontaneous mutation rates in null and band-morph mutations of enzyme loci in Drosophila melanogaster.

Spontaneous mutations were accumulated for a total of 1,678,388 allele-generations in several hundred replicate second chromosome lines. These lines were compared of a Cy chromosome and one of three different lethal bearing chromosomes from natural populations. Electrophoretic mobility and/or activity change was screened for seven enzyme loci. Forty-four null mutations were detected, but no band-morph mutations were observed. There is significant variation in null mutation rate among enzyme loci and among lethal chromosomes. This may be attributable to differences in the distribution of transposable elements among the lines. The band-morph mutation rate is pooled with previous results and becomes 7.48 x 10(-7) with a 95% confidence limit of 2.04 x 10(-7) to 1.91 x 10(-6) per locus per generation. Similarly, the pooled null mutation rate becomes 1.30 x 10(-5) with 95% confidence limit of 1.15 x 10(-5) to 1.52 x 10(-5) per locus per generation.

Animals↗
PubMed2000

Prognostic value of p53 gene mutations and the product expression in de novo acute myeloid leukemia.

In acute myeloid leukemia (AML), p53 mutations are reportedly infrequent but associated with a poor prognosis. The majority of mutations are missense mutations, which generally lead to accumulation of nuclear p53 protein. However, the prognostic significance of the accumulation remains unknown in AML. In this study, we compared the prognostic value of p53 mutations versus accumulation of the product. p53 mutations were found in 9 (4.5%) of 200 patients with de novo AML. The p53 mutation detectable (mutation+) group had a worse prognosis (p = 0.0009) than the mutation not detectable (mutation-) group. Multivariate analysis showed that the p53 mutation was an independent factor (p = 0.005) for short overall survival as well as 60 yr or older (p = 0.001) and unfavorable karyotypes (p = 0.001). In 79 of the 200 patients, the expression of p53 was studied by immunocytochemistry (ICC) using anti-p53 monoclonal antibody (DO-7). All samples carrying missense mutations (N = 6) were positive for ICC in over 15% of nuclei of each sample, chosen as the optimized cutoff value of p53 accumulation. Accumulation was thus found in 14 of the 79 patients. However, there was no prognostic difference according to the accumulation, because the mutation-/accumulation+ group (N = 8) tended to have a good prognosis. These findings indicate that molecular detection of p53 mutations yields better prognostic information than ICC. In a subset of AML, p53 protein might be accumulated without mutation presumably due to upstream signals of p53.

Acute Disease↗
PubMed1998

A bovine respiratory syncytial virus strain with mutations in subgroup-specific antigenic domains of the G protein induces partial heterologous protection in cattle.

Bovine respiratory syncytial virus (BRSV) strains are tentatively divided in subgroups A, AB and B, based on antigenic differences of the G protein. A Dutch BRSV strain (Waiboerhoeve: WBH), could not be assigned to one of the subgroups, because the strain did not react with any monoclonal antibody against the G protein. We describe here that the WBH strain has accumulated critical mutations in subgroup-specific domains of the G protein gene, which also occur but then independently in G protein genes of BRSV subgroup A or B strains. Although the comparison of nucleotide residues 256-792 of the G gene of the WBH strain with those of subgroup A and B strains showed that the G gene of the WBH strain is different from that of BRSV subgroup A and B strains, the sequence divergence was not more than observed within the G genes of human respiratory syncytial virus subgroup A or B strains. The WBH strain did not induce severe disease after experimental infection of calves, and induced partial protection against a heterologous challenge. Despite the dissimilarity of the conserved central regions of the G protein of the WBH strain and that of the challenge strain, a secondary antibody response against this region was induced in WBH-infected calves after challenge. We conclude that complete BRSV virus can partially protect against a BRSV infection with a strain that contains an antigenic dissimilar G protein.

Amino Acid Sequence↗
PubMed2006

Dynamics of the peroxisomal import cycle of PpPex20p: ubiquitin-dependent localization and regulation.

We characterize the peroxin PpPex20p from Pichia pastoris and show its requirement for translocation of PTS2 cargoes into peroxisomes. PpPex20p docks at the peroxisomal membrane and translocates into peroxisomes. Its peroxisomal localization requires the docking peroxin Pex14p but not the peroxins Pex2p, Pex10p, and Pex12p, whose absence causes peroxisomal accumulation of Pex20p. Similarities between Pex5p and Pex20p were noted in their protein interactions and dynamics during import, and both contain a conserved NH2-terminal domain. In the absence of the E2-like Pex4p or the AAA proteins Pex1p and Pex6p, Pex20p is degraded via polyubiquitylation of residue K19, and the K19R mutation causes accumulation of Pex20p in peroxisome remnants. Finally, either interference with K48-branched polyubiquitylation or removal of the conserved NH2-terminal domain causes accumulation of Pex20p in peroxisomes, mimicking a defect in its recycling to the cytosol. Our data are consistent with a model in which Pex20p enters peroxisomes and recycles back to the cytosol in an ubiquitin-dependent manner.

Cytosol↗
PubMed2006

Interplay of selective pressure and stochastic events directs evolution of the MEL172 satellite DNA library in root-knot nematodes.

According to the library model, related species can have in common satellite DNA (satDNA) families amplified in differing abundances, but reasons for persistence of particular sequences in the library during long periods of time are poorly understood. In this paper, we characterize 3 related satDNAs coexisting in the form of a library in mitotic parthenogenetic root-knot nematodes of the genus Meloidogyne. Due to sequence similarity and conserved monomer length of 172 bp, this group of satDNAs is named MEL172. Analysis of sequence variability patterns among monomers of the 3 MEL172 satellites revealed 2 low-variable (LV) domains highly reluctant to sequence changes, 2 moderately variable (MV) domains characterized by limited number of mutations, and 1 highly variable (HV) domain. The latter domain is prone to rapid spread and homogenization of changes. Comparison of the 3 MEL172 consensus sequences shows that the LV domains have 6% changed nucleotide positions, the MV domains have 48%, whereas 78% divergence is concentrated in the HV domain. Conserved distribution of intersatellite variability might indicate a complex pattern of interactions in heterochromatin, which limits the range and phasing of allowed changes, implying a possible selection imposed on monomer sequences. The lack of fixed species-diagnostic mutations in each of the examined MEL172 satellites suggests that they existed in unaltered form in a common ancestor of extant species. Consequently, the evolution of these satellites seems to be driven by interplay of selective constraints and stochastic events. We propose that new satellites were derived from an ancestral progenitor sequence by nonrandom accumulation of mutations due to selective pressure on particular sequence segments. In the library of particular taxa, established satellites might be subject to differential amplification at chance due to stochastic mechanisms of concerted evolution.

Animals↗
PubMed2002

Immunohistochemistry of cyclin D1 and beta-catenin, and mutational analysis of exon 3 of beta-catenin gene in parathyroid adenomas.

Parathyroid adenomas are benign uniglandular tumors and are the most common cause of primary hyperparathyroidism. Several genetic changes in parathyroid tumors, including inactivation of tumor suppressor genes, activation of oncogenes and loss of heterozygosity at several chromosomal loci, have been reported. In this study, we analyzed the status of cyclin D1 and beta-catenin in 24 cases of parathyroid adenoma. Immunohistochemistry of cyclin D1 showed positive staining in 9 (37.5%) of the 24 parathyroid adenomas. The status of beta-catenin, which has recently been identified as a regulator of cyclin D1 transcription, was examined by direct sequencing of exon 3 of the beta-catenin gene and immunohistochemistry of beta-catenin protein, but neither mutation nor accumulation of beta-catenin was detected in any of the cases. These results indicate that cyclin D1 is frequently accumulated in parathyroid adenomas, independently of dysfunction in the Wnt signaling pathway.

Adenoma↗
PubMed1997

Mitochondrial involvement in the ageing process. Facts and controversies.

Mitochondria are believed to be involved in human ageing. Whilst it is clear that various mitochondrial DNA mutations do accumulate in human tissues with age, whether or not they interfere with respiratory chain function is uncertain. We question the results of previous studies which have measured respiratory chain function in human skeletal muscle with age. Whilst cytochrome c oxidase deficient fibres are a real finding in skeletal muscle, the contribution of mitochondrial DNA mutations to human ageing is still controversial. Our results show for mitochondria to be involved in ageing then it must be through a more subtle mechanism than a global decline in respiratory chain function.

Aging↗
PubMed2004

Mutations conferring drug resistance affect eukaryotic expression of HIV type 1 reverse transcriptase.

Mutations in reverse transcriptase (RT) confer high levels of HIV resistance to drugs. However, while conferring drug resistance, they can lower viral replication capacity (fitness). The molecular mechanisms behind remain largely unknown. The aim of the study was to characterize the effect of drug-resistance mutations on HIV RT expression. Genes encoding AZT-resistant RTs with single or combined mutations D67N, K70R, T215F, and K219Q, and RTs derived from drug-resistant HIV-1 strains were designed and expressed in a variety of eukaryotic cells. Expression in transiently transfected cells was assessed by Western blotting and immunofluorescent staining with RT-specific antibodies. To compare the levels of expression, mutated RT genes were microinjected into the nucleus of the oocytes of Xenopus laevis. Expression of RT was quantified by sandwich ELISA. Relative stability of RTs was assessed by pulse-chase experiments. Xenopus oocytes microinjected with the genes expressed 2-50 pg of RT mutants per cell. The level of RT expression decreased with accumulation of drug-resistance mutations. Pulse-chase experiments demonstrated that poor expression of DR-RTs was due to proteolytic instability. Instability could be attributed to additional cleavage sites predicted to appear in the vicinity of resistance mutations. Accumulation of drug-resistance mutations appears to affect the level of eukaryotic expression of HIV-1 RT by inducing proteolytic instability. Low RT levels might be one of the determinants of impaired replication fitness of drug-resistant HIV-1 strains.

Animals↗
PubMed2001

Deficient DNA mismatch repair: a common etiologic factor for colon cancer.

Hereditary non-polyposis colon cancer (HNPCC), the most common form of hereditary colon cancer, is a syndrome of deficient DNA mismatch repair (MMR). Five, possibly six, human MMR genes have been identified that, when mutated in the germline, cause susceptibility to this syndrome. To date, more than 300 different predisposing mutations are known, mainly affecting the MMR genes MLH1 ( approximately 50%), MSH2 ( approximately 40%) and MSH6 ( approximately 10%). Genetically predisposed individuals carry a defective copy of an MMR gene in every cell. Somatic inactivation of the remaining wild-type copy in a target tissue, typically colon, gives rise to a profound repair defect, progressive accumulation of mutations and cancer. Instability at short tandem repeat sequences, microsatellites, is a typical manifestation of MMR deficiency and apart from HNPCC tumors, occurs in approximately 15% of sporadic colon and other tumors. The majority of the latter cases are attributable to one particular MMR gene, MLH1, and unlike HNPCC, an epigenetic rather than a genetic mechanism plays an important role in the inactivation of this gene. The present review provides an update of the genetics of HNPCC and more generally, of cancer development driven by deficient MMR. Recent discoveries suggest that apart from post-replication repair, MMR proteins have several other functions that are highly relevant to carcinogenesis. Knowledge of the complex interplay between the MMR system and other cellular pathways allows us to better understand the phenotypic manifestations of HNPCC and other cancers with deficient MMR.

Base Pair Mismatch↗
PubMed2002

Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations.

Plasmodium falciparum chloroquine resistance is a major cause of worldwide increases in malaria mortality and morbidity. Recent laboratory and clinical studies have associated chloroquine resistance with point mutations in the gene pfcrt. However, direct proof of a causal relationship has remained elusive and most models have posited a multigenic basis of resistance. Here, we provide conclusive evidence that mutant haplotypes of the pfcrt gene product of Asian, African, or South American origin confer chloroquine resistance with characteristic verapamil reversibility and reduced chloroquine accumulation. pfcrt mutations increased susceptibility to artemisinin and quinine and minimally affected amodiaquine activity; hence, these antimalarials warrant further investigation as agents to control chloroquine-resistant falciparum malaria.

ATP-Binding Cassette Transporters↗
PubMed1993

Accumulation of mtDNA with a mutation at position 3271 in tRNA(Leu)(UUR) gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function.

A new mitochondrial DNA (mtDNA) mutation of tRNA(Leu)(UUR) at nucleotide position 3271 (MELAS3271) was determined to be involved in the pathogenic process of mitochondrial diseases MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) using intercellular transfer of patient-derived mtDNA to mtDNA-less HeLa cells (rho 0 HeLa cells). Cybrid clones containing imported mtDNA exclusively from a MELAS patient with MELAS3271 mtDNA were isolated, and the influence of MELAS3271 mtDNA on mitochondrial translation activity and mitochondrial respiratory complex I enzyme activity were examined. Accumulation of more than 87% MELAS3271 mutant mtDNA in the cybrid clones induced both low complex I activity and abnormal mtDNA-encoded polypeptide synthesis including at least complex I subunit ND6. suggesting involvement of the new MELAS-associated mutation in the pathogenesis.

Blotting, Southern↗