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PubMed2002

Typing of Pasteurella multocida isolated from pigs with and without porcine dermatitis and nephropathy syndrome.

Porcine dermatitis and nephropathy syndrome (PDNS) is a sporadic, usually fatal disease of growing and finishing pigs that has been recognized in many pig-producing countries. Pasteurella multocida strains isolated from 15 pigs with PDNS and 51 pigs without PDNS were characterized by capsule and somatic antigen typing, random amplified polymorphic DNA (RAP-D) typing, and restriction analysis of genomic DNA using pulsed-field gel electrophoresis (PFGE). While capsular, somatic, and RAP-D typing did not discriminate PDNS isolates from non-PDNS isolates, all of the isolates from PDNS cases showed an identical ApaI PFGE restriction pattern. This pattern was also found in a high proportion (36%) of P. multocida strains isolated from non-PDNS cases. Isolation of a single variant of P. multocida from tissues of pigs with PDNS warrants further investigation into the possible role of these bacteria in the etiology of the disease.

Animals↗
PubMed1992

Epidermal nevus syndrome: subgroup with neuronal migration defects.

Epidermal nevus syndrome is one of the sporadic congenital hamartoses in which neurologic abnormalities have been frequently reported. We report two cases with severe primary brain involvement, seizures, mental retardation, and facial hemihypertrophy. We emphasize the superiority of magnetic resonance imaging over other radiographic studies in outlining the primary central nervous system anomalies associated with this syndrome. Although attempts were made to distinguish between several variants of epidermal nevus syndrome, it is clear that these are one entity. Proteus syndrome, encephalocraniocutaneous lipomatosis, and epidermal nevus syndrome have several overlapping phenotypic features. We suggest that they represent a phenotypic continuum, which in turn suggests a common pathogenetic process. While the cause of these syndromes is unknown, observations point to a somatic mutation leading to variable patterns of mosaicism.

Abnormalities, Multiple↗
PubMed1999

Frequent allelic loss at chromosome 3p distinct from genetic alterations of the 8-oxoguanine DNA glycosylase 1 gene in head and neck cancer.

Cigarette smoking is the major known risk factor for head and neck cancer. Tobacco promotes oxidative stress and enhances tissue levels of 8-hydroxyguanine (8-OH-G) in smokers. The presence of 8-OH-G does not impede replication but leads to an accumulation of G-->T transversions. Recently, the gene for human 8-oxoguanine DNA glycosylase 1 (hOGG1), an enzyme involved in the repair of 8-OH-G in humans, was cloned and mapped to chromosome 3p. In head and neck tumors, the hOGG1 gene locus is often targeted by loss of heterozygosity (LOH), and the spectrum of mutations in the p53 gene shows a bias in favor of G:C-->T:A transversions, as would be expected if HOGG1 repair functions were disabled. To test the involvement of hOGG1 in head and neck carcinogenesis, we had previously screened 56 tumors for LOH at 3p. From these tumors and two others, we selected 33 tumors demonstrating LOH for further mutational analysis of this gene. No somatic inactivating mutation was found in hOGG1. Polymorphisms involving intron 4 and exon 7 were present in 30% of the patients. A new polymorphism was identified in one patient in exon 6 and led to the amino-acid change G308E. Similar repair activities were found for the wild-type and exon 6-variant enzymes. Therefore, the involvement of hOGG1 in head and neck carcinogenesis is not strongly supported by this work.

Alleles↗
PubMed1993

Residues that mediate DNA binding of autoimmune antibodies.

Somatic mutations to arginine (R) are a common feature of a subset of J558 H chain genes that code for the majority of high-affinity, anti-dsDNA antibodies in autoimmune MRL/lpr mice. To examine the consequences of such amino acid substitutions on DNA binding, we reverted three somatic mutations of a prototypic anti-dsDNA H chain gene, VH3H9, and assayed the effect of those reversions by expression in a V lambda 1 L chain-only plasmacytoma line. Reversion of R53 eliminated virtually all dsDNA binding and sharply reduced ssDNA affinity. While the complete germ-line revertant of VH3H9 retained a low level of DNA binding, the substitution of R96, a product of N base addition in the third complementarity determining region (CDR3), with glycine (G) was sufficient to abolish measureable DNA specificity. Antibodies with higher affinity for DNA were generated by introducing arginines into VH3H9 at any one of four positions where somatic mutations to arginine had been identified by sequencing other anti-dsDNA J558 H chain genes. All four arginine mutants showed affinity increments consistent with their direct involvement in DNA binding, although one such mutant, K64R, required the simultaneous reversion of an adjacent aspartic acid (D) to the germ-line glycine. Two variants with three nongerm-line arginines showed further improvements in DNA affinity suggesting that their contributions to DNA binding may be additive. Molecular modeling of antibody and mutant F(ab) structures and calculations of their electrostatic potentials were used as an aid in interpreting the results and in predicting the location and size of possible combining sites.

Amino Acid Sequence↗
PubMed2000

Lack of somatic mutation in the coding sequence of SIAH1 in tumors hemizygous for this candidate tumor suppressor gene.

The human homolog of the Drosophila seven in absentia gene (SIAH1) may play an important role in apoptosis and tumor suppression. Transcription of SIAH1 is up-regulated in non-tumorigenic clonal populations of cells derived from 2 different tumorigenic parental cell lines. Intracellular SIAH1 mRNA concentration increases in intestinal cells as they migrate from the bottom of the crypt to the lumen, where they undergo apoptosis. Finally, SIAH1 is located on chromosome 16q12-q13, a region that is frequently deleted in a large variety of human tumors. These observations suggest SIAH1 as a candidate tumor suppressor gene that may be inactivated during tumorigenesis. To test this hypothesis, a search for mutation in the coding sequence of this gene was initiated in tumors exhibiting loss of heterozygosity (LOH) at 16q12-q13. No difference was found in 12 hepatocellular carcinomas, 19 breast carcinomas, 9 prostate carcinomas, 7 colon carcinomas and 5 human cell lines derived from colon cancer. One silent sequence variant (C to T transition at amino acid 270) was observed in the FET colon carcinoma cell line. It was subsequently found once in a group of 100 unrelated individuals from the CEPH families. A rapid real-time quantitative RT-PCR fluorescent method shows that SIAH1 remained transcriptionally active in the 6 colon cancer-derived cell lines, and the expression is comparable to the normal colon tissue. Taken together, these observations suggest that although many tumors may have lost one SIAH1 allele, the second allele would not be the site of frequent somatic mutations and may even remain functional.

Alleles↗
PubMed1984

Uridine kinase molecular species and uridine uptake in some variants of rat hepatomas.

In a family of clonal lines derived from the Reuber H 35 rat hepatoma, four electrophoretically distinct molecular forms of uridine kinase (UK I, II, III, and IV) have been characterized. They are the same as those found in foetal rat liver. Different UK profiles occur in these cell lines, and no strict correlation could be established between the state of differentiation of the cells and the form of UK expressed. A clone of somatic hybrid cells between line p4 (form 1 only) and Fu5-5 (forms II, III, and IV) that does not express form I indicates that p4 cells may lack a factor controlling the polymerization of form I. This variety of clonal cell lines was used to study the uptake and phosphorylation of labeled uridine. The results suggest a relationship between the UK form present and the rate uridine phosphorylation by the intact cells.

Animals↗
PubMed2026

Genomic Characterization of ETV6::RUNX1-Positive Childhood B-ALL in a Chinese Cohort: Novel Fusion Partners, Co-Occurring Mutations, and Risk-Stratifying Biomarkers.

BACKGROUND: ETV6::RUNX1 is the most common genetic abnormality in pediatric B-cell acute lymphoblastic leukemia (ALL; ∼25%), yet the comprehensive genetic architecture and molecular predictors of intermediate-risk (IR) stratification remain incompletely characterized. METHODS: We performed whole-transcriptome sequencing (Illumina NovaSeq 6000, rRNA depletion, 41.70 Gb/sample) on bone marrow samples from 93 pediatric ETV6::RUNX1-positive B-ALL patients. Bioinformatics analysis included STAR alignment, MuTect2 variant calling, FusionCatcher fusion detection, and VEP annotation. The Jaccard index with permutation testing assessed mutation co-occurrence; logistic regression identified independent predictors of IR classification. RESULTS: Beyond ETV6::RUNX1, we identified 51 distinct fusion genes across the cohort, including the reciprocal RUNX1-ETV6 (73.1%), chr8::KLF1210 (38.7%), and KLF12-chr8 (34.4%). Somatic mutations in 249 genes were detected; the most frequent were KIAA1715 (17.2%), KRAS (11.8%), and NSD2 (10.8%). Network analysis revealed significant chromatin modifier co-occurrence (KIAA1715-KMT2C: J = 0.136, p = 0.015) and KRAS-NRAS mutual exclusivity (J = 0.000, p = 0.042). PTCH1 (OR = 3.50, 95% CI 0.21-58.49, p = 0.41) and GNB1 (OR = 6.5, 95% CI 1.2-34.8, p = 0.029) mutations independently predicted IR classification. chr8::KLF1210 fusion correlated with higher Day-19 MRD levels (p = 0.038). CONCLUSIONS: GNB1 mutation represents a novel independent predictor of IR stratification in ETV6::RUNX1-positive B-ALL. The chromatin modifier co-occurrence module and extensive fusion architecture reveal biological heterogeneity within this favorable-risk subtype, with potential implications for risk-adapted therapeutic strategies.

B‐ALL↗
PubMed2005

Alterations of pre-mRNA splicing in cancer.

Recent genomewide analyses of alternative splicing (AS) indicate that up to 70% of human genes may have alternative splice forms, suggesting that AS together with various posttranslational modifications plays a major role in the production of proteome complexity. Splice-site selection under normal physiological conditions is regulated in the developmental stage in a tissue type-specific manner by changing the concentrations and the activity of splicing regulatory proteins. Whereas spliceosomal errors resulting in the production of aberrant transcripts rarely occur in normal cells, they seem to be an intrinsic property of cancer cells. Changes in splice-site selection have been observed in various types of cancer and may affect genes implicated in tumor progression (for example, CD44, MDM2, and FHIT) and in susceptibility to cancer (for example, BRCA1 and APC). Splicing defects can arise from inherited or somatic mutations in cis-acting regulatory elements (splice donor, acceptor and branch sites, and exonic and intronic splicing enhancers and silencers) or variations in the composition, concentration, localization, and activity of regulatory proteins. This may lead to altered efficiency of splice-site recognition, resulting in overexpression or down-regulation of certain splice variants, a switch in splice-site usage, or failure to recognize splice sites correctly, resulting in cancer-specific splice forms. At least in some cases, changes in splicing have been shown to play a functionally significant role in tumorigenesis, either by inactivating tumor suppressors or by gain of function of proteins promoting tumor development. Moreover, cancer-specific splicing events may generate novel epitopes that can be recognized by the host's immune system as cancer specific and may serve as targets for immunotherapy. Thus, the identification of cancer-specific splice forms provides a novel source for the discovery of diagnostic or prognostic biomarkers and tumor antigens suitable as targets for therapeutic intervention.

Exons↗
PubMed2026

Somatic Mitochondrial-Nuclear DNA Transfer in Lymphoproliferative Disorders.

INTRODUCTION: Somatic mitochondrial-nuclear DNA transfer (SMNT) is a process by which mitochondrial DNA (mtDNA), of varying sizes, integrate into the nuclear genome and has been previously reported in solid tumours. METHODS: EuroClonality-NGS DNA Capture sequencing data from 755 lymphoid malignancies and 59 lymphoid cell lines were analysed for SMNT-associated structural variants. RESULTS: Five malignancies (0.66%) harboured SMNTs, predominantly involving IGH genes, with one PTEN gene disruption identified. Breakpoint features supported non-homologous end joining-mediated integration. CONCLUSION: SMNTs are rare but recurrent events in lymphoid malignancies and may represent stable clonal markers for minimal residual disease monitoring. TRIAL REGISTRATION: The authors have confirmed clinical trial registration is not needed for this submission.

Journal Article↗
PubMed2005

How to pack the genome for a safe trip.

The transformation of the somatic chromatin into a unique and highly compact structure occurring during the post-meiotic phase of spermatogenesis is one of the most dramatic known processes of chromatin remodeling. Paradoxically, no information is available on the mechanisms controlling this specific reorganization of the haploid cell genome. The only existing hints suggest a role for histone variants, as well as for stage-specific post-translational histone modifications,before and during the incorporation of testis-specific basic nuclear proteins. Moreover, the exact functions of the latter remain obscure. This chapter summarizes the major chromatin-associated events taking place during the post-meiotic differentiation of male haploid cells in mammals and discusses some of the basic issues that remain to be solved to finally understand chromatin remodeling during spermatogenesis.

Animals↗
PubMed2000

RET proto-oncogene mutations in thyroid carcinomas: clinical relevance.

Different forms of RET mutations are found in papillary and medullary thyroid carcinomas. Rearrangements with other genes (RET/PTC oncogene) play a causative role in a significant proportion of papillary thyroid carcinomas. In this case, several factors influence the frequency and the type of RET/PTC, such as exposure to radiation, age and histological variant of the papillary tumor. On the other hand, the presence of the mutation does not seem to influence the biological behavior of the tumor or its response to conventional treatment modalities. In the setting of medullary thyroid cancer, germline RET point-mutations are implicated in the pathogenesis of virtually all hereditary forms and somatic point-mutations in nearly half of the sporadic forms. The clinical impact of this finding is that family members at-risk of hereditary MTC may be screened by genetic analysis, to distinguish those carrying or not-carrying the mutation. The last can be reassured on their status and relieved from further follow-up. Those with the mutation may be treated at a pre-clinical stage of the disease or even before the disease is started. The present review is focused on the clinical implication of RET gene mutations in thyroid cancer patients.

Carcinoma, Medullary↗
PubMed2003

Chromosomal proteins in the spermatogenesis of Drosophila.

Chromatin constitution in the male germ line of Drosophila is discussed with respect to the substitution of somatic histones by protamines or other basic proteins. The specific properties of germ line chromatin include the initiation and completion of the spermatogenic pathway and the reprogramming of the genome for embryonic development. During meiotic prophase cell cycle-regulated H3 histones appear to a large extent to be substituted by the histone H3.3 replacement variant protein, which is generally found associated with transcriptionally active chromatin. Condensation of the chromosomes during meiosis and the subsequent compaction for packaging in the sperm head require suitable proteins, but the cell cycle-regulated histones are not available as their expression is limited to S-phase. It is, therefore, proposed that any basic protein with a limited range of sequence requirements may take over this packaging function. Suitable proteins may have evolved by divergence from histone variants not restricted in their expression to S-phase, similar to the testes-predominant histone H3.3A of Drosophila.

Animals↗
PubMed2005

Ionizing radiation and genetic risks XIV. Potential research directions in the post-genome era based on knowledge of repair of radiation-induced DNA double-strand breaks in mammalian somatic cells and the origin of deletions associated with human genomic disorders.

Recent estimates of genetic risks from exposure of human populations to ionizing radiation are those presented in the 2001 report of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). These estimates incorporate two important concepts, namely, the following: (1) most radiation-induced mutations are DNA deletions, often encompassing multiple genes, but only a small proportion of the induced deletions is compatible with offspring viability; and (2) the viability-compatible deletions induced in germ cells are more likely to manifest themselves as multi-system developmental anomalies rather than as single gene disorders. This paper: (a) pursues these concepts further in the light of knowledge of mechanisms of origin of deletions and other rearrangements from two fields of contemporary research: repair of radiation-induced DNA double-strand breaks (DSBs) in mammalian somatic cells and human molecular genetics; and (b) extends them to deletions induced in the germ cell stages of importance for radiation risk estimation, namely, stem cell spermatogonia in males and oocytes in females. DSB repair studies in somatic cells have elucidated the roles of two mechanistically distinct pathways, namely, homologous recombination repair (HRR) that utilizes extensive sequence homology and non-homologous end-joining (NHEJ) that requires little or no homology at the junctions. A third process, single-strand annealing (SSA), which utilizes short direct repeat sequences, is considered a variant of HRR. HRR is most efficient in late S and G2 phases of the cell cycle and is a high fidelity mechanism. NHEJ operates in all cell cycle phases, but is especially important in G1. In the context of radiation-induced DSBs, NHEJ is error-prone. SSA is also an error-prone mechanism and its role is presumably similar to that of HRR. Studies in human molecular genetics have demonstrated that the occurrence of large deletions, duplications or other rearrangements in certain regions of the genome is related to the presence of large segments of repetitive DNA called segmental duplications (also called duplicons or low copy repeats, LCRs) in such regions. The mechanism that is envisaged for the origin of deletions and other rearrangements involves misalignment of region-specific LCRs of homologous chromosomes in meiosis followed by unequal crossing-over (i.e., non-allelic homologous recombination, NAHR). We hypothesize that: (a) in spermatogonial stem cells, NHEJ is probably the principal mechanism underlying the origin of radiation-induced deletions, although SSA and NAHR may also be involved to some extent, especially at low doses; and (b) in irradiated oocytes, NAHR is likely to be the main mechanism for generating deletions. We suggest future research possibilities, including the development of models for identifying regions of the genome that are susceptible to radiation-induced deletions. Such efforts may have particular significance in the context of the estimation of genetic risks of radiation exposure of human females, a problem that is still with us.

Animals↗
PubMed2002

Cell cycle-dependent localization of macroH2A in chromatin of the inactive X chromosome.

One of several features acquired by chromatin of the inactive X chromosome (Xi) is enrichment for the core histone H2A variant macroH2A within a distinct nuclear structure referred to as a macrochromatin body (MCB). In addition to localizing to the MCB, macroH2A accumulates at a perinuclear structure centered at the centrosome. To better understand the association of macroH2A1 with the centrosome and the formation of an MCB, we investigated the distribution of macroH2A1 throughout the somatic cell cycle. Unlike Xi-specific RNA, which associates with the Xi throughout interphase, the appearance of an MCB is predominantly a feature of S phase. Although the MCB dissipates during late S phase and G2 before reforming in late G1, macroH2A1 remains associated during mitosis with specific regions of the Xi, including at the X inactivation center. This association yields a distinct macroH2A banding pattern that overlaps with the site of histone H3 lysine-4 methylation centered at the DXZ4 locus in Xq24. The centrosomal pool of macroH2A1 accumulates in the presence of an inhibitor of the 20S proteasome. Therefore, targeting of macroH2A1 to the centrosome is likely part of a degradation pathway, a mechanism common to a variety of other chromatin proteins.

Animals↗
PubMed1997

Glycophorin A somatic cell mutation frequencies in residents of Tibet at high altitudes.

Since cosmic radiation is absorbed by the atmosphere surrounding the Earth, people who live at high altitude receive significantly larger amounts of cosmic radiation exposure than do those who live at low altitude. The glycophorin A-based somatic mutation assay was performed on 36 blood samples from two populations of Tibet inhabitants to determine whether residents at high altitude (4,300 m) accumulate more somatic mutations than do those who live at low altitude (1,500-1,900 m). These two populations differ in estimated cumulative lifetime cosmic radiation dose, with high altitude residents having received a mean of 111 mSv while low altitude residents received a mean of 27 mSv. Results showed no significant difference in peripheral blood variant erythrocyte frequency between these two populations and no difference from results of a previous study on Finnish workers who live at very low altitude (<500 m).

Altitude↗
PubMed2004

Heterodimerization and endocytosis of Arabidopsis brassinosteroid receptors BRI1 and AtSERK3 (BAK1).

In Arabidopsis thaliana brassinosteroid (BR), perception is mediated by two Leu-rich repeat receptor-like kinases, BRASSINOSTEROID INSENSITIVE1 (BRI1) and BRI1-ASSOCIATED RECEPTOR KINASE1 (BAK1) (Arabidopsis SOMATIC EMBRYOGENESIS RECEPTOR-like KINASE3 [AtSERK3]). Genetic, biochemical, and yeast (Saccharomyces cerevisiae) interaction studies suggested that the BRI1-BAK1 receptor complex initiates BR signaling, but the role of the BAK1 receptor is still not clear. Using transient expression in protoplasts of BRI1 and AtSERK3 fused to cyan and yellow fluorescent green fluorescent protein variants allowed us to localize each receptor independently in vivo. We show that BRI1, but not AtSERK3, homodimerizes in the plasma membrane, whereas BRI1 and AtSERK3 preferentially heterodimerize in the endosomes. Coexpression of BRI1 and AtSERK3 results in a change of the steady state distribution of both receptors because of accelerated endocytosis. Endocytic vesicles contain either BRI1 or AtSERK3 alone or both. We propose that the AtSERK3 protein is involved in changing the equilibrium between plasma membrane-located BRI1 homodimers and endocytosed BRI1-AtSERK3 heterodimers.

Arabidopsis↗
PubMed2003

Colorectal tumourigenesis in carriers of the APC I1307K variant: lone gunman or conspiracy?

The APC I1307K allele is believed to predispose to multiple colorectal tumours because the change at the nucleotide level-A(3)TA(4) to A(8)-creates a hypermutable site. Slippage of the A(8) tract undoubtedly occurs more often than expected in the tumours of I1307K carriers, but many of these tumours do not harbour changes at this site. Outside the A(8) tract, the tumours of I1307K carriers appear to harbour fewer somatic frameshift mutations than expected. There is inconsistent evidence as to whether or not I1307K confers an increased risk of colorectal cancer. Most I1307K patients and families who have undergone analysis of somatic APC mutations have been highly selected. It is therefore possible that many APC I1307K carriers with multiple adenomas have a susceptibility to tumours additional to that resulting from the A(8) tract.

Adenoma↗
PubMed1998

Mapping of the CYP2J cytochrome P450 genes to human chromosome 1 and mouse chromosome 4.

CYP2J subfamily cytochromes P450 catalyze the NADPH-dependent oxidation of arachidonic acid to several unique eicosanoids that possess numerous biological activities including modulation of ion transport, control of bronchial and vascular smooth muscle tone, and stimulation of peptide hormone secretion. We have identified sequence variants in the 3' untranslated regions of two mouse Cyp2j genes (Cyp2j5 and Cyp2j6) and used a PCR-based oligonucleotide hybridization assay to map both genes to the central region of chromosome 4 distal to the Jun oncogene. The corresponding human CYP2J gene (CYP2J2) has been assigned to human chromosome 1 on a panel of somatic hybrid cell lines and to 1p31.3-p31.2 by fluorescence in situ hybridization analysis. The proximity of the Cyp2j cluster to the Cyp4a cluster suggests that these genes may be part of a cassette of P450 genes involved in the oxidation of fatty acids.

Animals↗