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PubMed2003

BUB1 infrequently mutated in human breast carcinomas.

The BUB1 gene is a key player in the mitotic spindle checkpoint machinery that monitors proper segregation of sister chromatides during mitosis. It has been suggested that mutations in BUB1 may disrupt the spindle checkpoint and thereby cause chromosomal instability, which is a hallmark of solid tumors including those from the breast. From a series of breast carcinomas we selected 20 cases with genomic instability, as scored by Comparative Genome Hybridization (CGH), and without somatic TP53 (p53) mutations, and sequenced the entire coding region of the BUB1 gene. Two different constitutional sequence variants were found; a base substitution in exon 5, c.481G>A (CAG>CAA, a synonymous change encoding Gln144) in two samples, and a base substitution 8 bp upstream of exon 10, c.1007-8T>C in two other samples. No somatic mutations were detected. These results indicate that genomic instability scored as copy number alterations by CGH in TP53 wild type breast carcinomas is not caused by somatic mutations in the BUB1 gene.

Breast Neoplasms↗

PubMed1997

Spermatid-specific overexpression of the TATA-binding protein gene involves recruitment of two potent testis-specific promoters.

The gene encoding the TATA-binding protein, TBP, is highly overexpressed during the haploid stages of spermatogenesis in rodents. RNase protection analyses for mRNAs containing the previously identified first, second, and eighth exons suggested that most TBP mRNAs in testis did not initiate at the first exon used in somatic cells (here designated exon 1C). Using a sensitive ligation-mediated cDNA amplification method, 5' end variants of TBP mRNA were identified, and the corresponding cDNAs were cloned from liver and testis. In liver, a single promoter/first exon is used to generate a steady-state level of roughly five molecules of TBP mRNA per diploid cell equivalent. In testis, we detect modest up-regulation of the somatic promoter and recruitment of at least five other promoters. Three of the alternative promoter/first exons, including 1C and two of the testis-specific promoter/first exons, 1D and 1E, contribute roughly equivalent amounts of mRNA which, in sum, account for greater than 90% of all TBP mRNA in testis. As a result, round spermatids contain an estimated 1000 TBP mRNA molecules per haploid cell. Testis TBP mRNA also exhibits several low abundance 5' end splicing variants; however, all detected TBP mRNA leader sequences splice onto the common exon 2 and are expected to initiate translation at the same site within exon 2. The precise locations of the three major initiation exons are mapped on the gene. The identification of the strong testis-specific promoter/first exons will be important for understanding spermatid-specific tbp gene regulation.

Animals↗

PubMed1995

Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analyses.

In order to characterize the dynamics of CTG repeat instability in somatic and germline tissue from myotonic dystrophy (DM) males we have used small pool polymerase chain reaction (PCR) in a detailed quantitative analysis of repeat length variation. We demonstrate that the heterogeneous smear of CTG repeats observed in DM patients using standard analyses is comprised of multiple unresolved bands that may be dissected into discrete length alleles derived from single cells using single molecule PCR techniques. Analysis of somatic tissues demonstrates a bias toward increasing allele length and a lower boundary below which variant alleles are rare, consistent with a highly directional expansion pathway in the soma. Two sperm samples show extensive variation and a size increase bias, concordant with the phenomenon of anticipation. In addition, sperm analysis shows that large contractions, including reversions into the normal size range, are restricted to the germline. Detailed analysis of intergenerational 'reductions' paternally transmitted to two offspring suggests that some apparent reductions may be artifacts of somatic expansion in the parent. Our data indicate that in addition to germline variation, substantial somatic expansion can also contribute to the intergenerational differences usually observed in DM.

Adult↗

PubMed2002

Somatic mutation and SNP in the promoter of dbpA and human hepatocarcinogenesis.

Human DNA-binding protein (dbpA) is a member of a Y-box binding protein family containing a cold shock domain. The increased expression of Y box binding proteins in somatic cells is associated with cell proliferation and transformation. Recently, we isolated a splicing variant of dbpA as a candidate for the cellular recombinogenic protein that leads to genomic instability and inflammation-mediated hepatocarcinogenesis. The expression of dbpA is enhanced in proliferating cells, but the manner in which it regulates transcription is largely unknown. In this study, we analyzed the transcriptional regulatory region of dbpA, and searched for the mutation in this region by a direct sequence method. In 3 of 55 human hepatocellular carcinoma (HCC) cases, we identified one nucleotide replacement (T right curved arrow G transversion) in nucleotide position -6 of the promoter region. Among 3 cases showing this transversion, one HCC case was due to a somatic mutation and the other two were due to single nucleotide polymorphism (SNP). By luciferase assay, we showed that the transcriptional activity of the promoter region with the transversion was significantly higher than that of the wild-type. Using the Southwestern blotting, we also confirmed the existence of a cellular proteins (about 25 and 50 kDa) that specifically bind to the sequence with this transversion. Our results suggested the biological significance of the transversion of dbpA's promoter region as one of the factors accelerating hepatocarcinogenesis.

Base Sequence↗

PubMed2001

Germline sequence variant S836S in the RET proto-oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population.

OBJECTIVE: The molecular basis of sporadic medullary thyroid carcinoma (MTC) remains elusive. While germline gain-of-function mutations in the RET proto-oncogene cause hereditary MTC, somatic activating RET mutations and loss of heterozygosity of markers in various chromosomal regions representing deletions of tumour suppressor genes, have been described in a variable number of sporadic MTC. A previous report suggested that the presence of a germline variant at RET codon 836 (S836S) was associated with the development of sporadic MTC and, furthermore, that the presence of S836S was highly correlated with somatic RET M918T mutation in the MTC. Thus, we sought to determine if the S836S variant would be associated with sporadic MTC from a completely different population base, that of Andalucia. DESIGN: This is a case-control study to determine whether the presence of RET germline S836S is correlated with sporadic MTC in Andalucia. PATIENTS: Thirty-two patients with sporadic MTC from the Andalucia region of Spain, serviced by our University Hospital, were ascertained throughout the period 1995-99. Sporadic MTC was defined as a lack of personal or family history suggestive of multiple endocrine neoplasia type 2 (MEN 2) and lack of germline RET mutations which define any MEN 2 subtype. A region and race matched cohort of 250 controls was also obtained. MEASUREMENTS: The frequency of the S836S allele was determined in cases and controls and compared using the standard chi-squared statistic and Fisher's exact test. RESULTS: The polymorphic allele frequency at codon 836 in the control population (18/500 chromosomes, 3.6%) differed significantly from the MTC case cohort, 9.3% of case chromosomes (six of 64 alleles, Fisher's exact test, two-tailed, P = 0.043). CONCLUSIONS: Germline RET S836S variant is associated with a two- to three-fold risk of sporadic MTC in the Spanish population, in accordance with a previous study based on German cases. Our observations suggest that this phenomenon might be universal and not limited to Germany.

Adult↗

PubMed1983

Syndrome of polydactyly, cleft lip, lingual hamartomas, renal hypoplasia, hearing loss, and psychomotor retardation: variant of the Mohr syndrome or a new syndrome?

Three sibs, the proband and two monozygotic twins, have a condition including mental retardation, postnatal somatic retardation, preaxial polydactyly of the feet, bifid third metacarpal, median cleft lip, fatty hamartomas on the dorsum of the tongue, conductive hearing loss, and unilateral or bilateral renal agenesis. This probably autosomal recessive syndrome could be a further example of the condition described by Váradi et al or a variant of the Mohr syndrome.

Abnormalities, Multiple↗

PubMed1987

DNase I site mapping and micrococcal nuclease digestion of pachytene chromatin reveal novel structural features.

A comparison of the DNase I digestion products of the 32P-5'-end-labeled pachytene nucleosome core particles (containing histones H2A, TH2A, X2, H2B, TH2B, H3, and H4) and liver nucleosome core particles (containing somatic histones H2A, H2B, H3, and H4) revealed that the cleavage sites that are 30, 40, and 110 nucleotides away from the 5'-end are significantly more accessible in the pachytene core particles than in the liver core particles. These cleavage sites correspond to the region wherein H2B interacts with the nucleosome core DNA. These results, therefore, suggest that the histone-DNA interaction at these sites in the pachytene core particles is weaker, possibly because of the presence of the histone variant TH2B interacting at similar topological positions in the nucleosome core as that of its somatic counterpart H2B. Such a loosened structure may also be maintained even in the native pachytene chromatin since micrococcal nuclease digestion of pachytene nuclei resulted in a higher ratio of subnucleosomes (SN4 + SN7) to mononucleosomes than that observed in liver chromatin.

Animals↗

PubMed1986

Idiotype variant cell populations in patients with B cell lymphoma.

Using isolated idiotype (Id) protein we generated panels of antibodies in two patients with follicular lymphoma, one of whom had never received prior chemo-or radiotherapy. Flow cytometry and frozen section tissue staining of tumor with these monoclonal antibodies (mAb) revealed multiple subpopulations within each tumor. Individual mAb stained between 7% and 83% of surface Ig+ cells in the tumor samples. These subpopulations were overlapping and no single antibody recognized all the tumor cells. However, combinations of antibodies seemed to capture total tumor in both cases. In some instances, the percentage of tumor stained by a single mAb varied over time, and differed between lymph nodes sampled at the same time. Because a single species of Id protein was used to generate mAb in each case, it appears that the antibodies were directed against idiotopes variably shared by different populations within each tumor, and this was confirmed by crossblocking studies. Tumor cells from one patient were fused to a nonsecreting heteromyeloma line K6H6/B5, and most of the resulting hybrids secreted Id protein. Four mAb were used to screen the Id proteins secreted by these hybrids, and 11 different variants (16 maximal) were found. Southern blot analysis of rearranged Ig genes was done in two hybrids and biopsy material. Identically rearranged light-chain genes were seen but it appeared as though extensive somatic variation had occurred in heavy chain genes. These studies indicate that: striking Id variation can exist at diagnosis in untreated patients, the percentage of tumor represented by an individual variant may change with time and may differ between tumor sampled from different anatomical locations, and somatic variation appears to be responsible for the observed heterogeneity. Although this degree of variation makes anti-Id antibody therapy more difficult, appropriate combinations of mAb should be more efficacious than single antibodies in such cases.

Adult↗

PubMed1989

Induction of tumor-cell lysis by bi-specific monoclonal antibodies recognizing renal-cell carcinoma and CD3 antigen.

Bi-specific monoclonal antibodies (MAbs) were developed by somatic hybridization of 2 mouse hybridomas, one producing MAb against the G250 renal-cell carcinoma (RCC)-associated antigen and the other against the T-cell antigen CD3 (OKT3). The dual specificity of the hybrid MAb produced by these so-called quadromas was analyzed by immunohistochemistry on tissue sections and by cytotoxicity assays with relevant target and effector cells. The bi-specific MAb could induce TCR alpha beta/CD3+ and TCR gamma delta/CD3+ cloned lymphocytes to kill RCC cells. A noteworthy finding was that the TCR alpha beta and gamma delta lymphocyte clones showed different triggering abilities. The specificity of target-cell lysis by the cytotoxic T cells (CTL) was dictated by the specificity of the G250 MAb. Control bi-specific MAb, recognizing a cell-surface structure not involved in T-cell activation, did not induce lysis. Several IgG subclass switch variants of the G250 hybridoma, i.e., IgG1, 2a, 2b and IgE, were used for somatic hybridization with the OKT3 hybridoma (IgG2a). Except for IgE, all IgG subclass combinations could equally induce cytolysis. Induction of cytolysis was inhibited only by excess OKT3 MAb. Comparison of 2 bi-specific MAb preparations of the same combination (IgG2a/1), produced by 2 quadromas derived from the same parental hybridomas after identical purification procedures, produced different amounts of bispecific MAb.

Animals↗

PubMed2026

Targeting DNA mismatch repair in Huntington's disease.

Somatic expansion of the HTT CAG repeat is a key feature of Huntington's disease (HD) pathogenesis. Mismatch repair (MMR) enzymes drive this process through erroneous DNA repair, with variants in MMR genes modifying the onset and progression of disease features. Cell-type-specific CAG repeat sizing recently confirmed that elevated somatic expansion underlies the selective vulnerability of HD medium spiny neurons, with expansion beyond certain CAG thresholds associated with distinct stages of cellular pathogenesis. In this review, we synthesise insights from post-mortem brain tissue, cell systems, and mouse models, detailing key CAG repeat-length-dependent changes. In addition, we critically evaluate the MMR proteins MSH3, MLH3, and PMS1 as therapeutic targets for slowing somatic expansion and outline key safety considerations for emerging MMR-modulating approaches.

Huntington Disease↗

PubMed2005

Hodgkin's disease variant of Richter's syndrome clonally related to chronic lymphocytic leukemia arises in ZAP-70 negative mutated CLL.

Chronic lymphocytic leukemia (CLL) may derive from either immunoglobulin V(H) gene unmutated (naïve) or mutated (antigen-experienced) post-germinal center B-cells. Richter's syndrome denotes the transformation of CLL into aggressive B-cell lymphoma. Most Richter's syndrome cases are secondary diffuse large B-cell lymphomas, but some are Hodgkin's disease variants. Hodgkin's lymphoma is thought to originate from germinal center or post-germinal center B-cells with evidence of somatic V(H) hypermutation. Taking into account CLL and Hodgkin's lymphoma histogenesis, hypothetically only CLL derived from V(H) mutated B-cells can clonally progress to Hodgkin's lymphoma variant of Richter's syndrome. To test our hypothesis, we analyzed the CLL ZAP-70 status as a surrogate for the V(H) mutational status in four patients with subsequent Hodgkin's disease variants of Richter's syndrome. In all three cases with proven or suspected clonal relationship between Hodgkin and Reed-Sternberg- and leukemia cells, the CLL samples remained negative for ZAP-70, corresponding to CLL histogenesis from V(H) mutated B-cells. These empirical data suggest that the histological and clinical diversity of Richter's transformation could be to a part explained by the different origin of CLL, with Hodgkin's disease variants arising probably only in V(H) mutated CLL.

Cell Transformation, Neoplastic↗

PubMed1983

Glucose-6-phosphate dehydrogenase as a probe for the study of X-chromosome inactivation in hunan females.

The electrophoretic variants of G6PD have provided evidence for a single active X-chromosome in human somatic cells, but two active X-chromosomes in germ cells and in triploid cells with a 69,XXY karyotype. Studies of clonal populations of cells heterozygous for G6PD-A but expressing a single isozyme have provided evidence that the maintenance of the inactivation process is extremely stable, but that an occasional localized derepression event may occur. Such populations have also been used to show that methylation of X-chromosome DNA is not obviously different for XA and XI; furthermore, methylation is surprisingly unstable at least at some sites on the X. Studies of derepressed loci on the inactive X-chromosome in these clonal cell populations show that the expression of loci that escape inactivation is greater on XA than XI. G6PD variants have provided significant insights into the consequences of X-chromosome inactivation, revealing the role of intercellular communication and cell selection in determining female phenotype. The evidence that is now available indicates that the regulation of the X-chromosome is complex. The mechanisms involved include: 1) initiation, an event that may be mediated through an autosomal product and 2) maintenance which is stable but subject to programmed derepression of the entire chromosome during ontogeny of germ cells and occasional unprogrammed localized derepression in somatic cells. In addition, there may be transcriptional differences between XI and XA to compensate for monosomy of X-linked genes. The molecular basis for this multilevel regulation is unclear, but it seems certain that the cloned DNA probe for G6PD [Persico et al, 1981] will provide further insights.

Alleles↗

PubMed1992

Complete amino acid sequence of the variable regions of two highly related heavy and light chains of human IgG (SFL) and IgM (RIV) rheumatoid factors.

The complete amino acid structure of the variable regions of two monoclonal human rheumatoid factors (RF), antibodies that bind to the Fc portion of IgG, is presented. Although these RFs are of different isotypes, IgG (SFL) and IgM (RIV), they are highly related. They probably derive from the same KIII light chain variable region used, but the heavy chains are derived from genes of the VHIII family that are probably evolutionarily related. An analysis of the level of somatic mutation reveals that antigen selection was probably involved in the maturation of these clones. These antibodies, although highly related, are not merely IgM to IgG switch variants which occurred independently in different individuals. Little is currently known about the structure of IgG RFs and this study indicates that the level of somatic mutation of SFL is similar to other autoantibodies or antiviral antibodies of the IgG isotype.

Amino Acid Sequence↗

PubMed1995

Hemifacial hyperplasia with meningeal involvement: a variant of proteus syndrome?

We report on a sporadic case of hemifacial hamartomatous hyperplasia. The patient is male, and has sebaceous nevus-like skin change, subcutaneous lipomatous mass, cranial bone hyperplasia, and bony change of meninges. His lesion involves the anterior half of the face and cranial base, and, medially, is delimited by the midline. No case has been found identical to this in the literature, particularly with respect to the unusual meningeal lesion. However, without this meningeal lesion the rest of the manifestations are not uncommon in Proteus syndrome. Also, this case may be an indication of somatic mosaicism, lethal in its nonmosaic state. Thus, this case may be thought of as a variant of Proteus syndrome.

Adolescent↗

PubMed2002

Methylation-sensitive RFLPs: characterisation of two oil palm markers showing somaclonal variation-associated polymorphism.

The occurrence of "mantled" somaclonal variants (approx. 5%), which display alterations in floral organ structure, among populations of somatic embryo-derived oil palms ( Elaeis guineensis Jacq.) currently hampers any scaling-up of clonal plant micropropagation. As a first step towards the identification of abnormality-discriminating markers, we have screened a set of 27 oil palm cDNA probes for methylation-sensitive restriction fragment length polymorphisms (RFLPs) using callus genomic DNA digested with the isoschizomeric enzymes MspI and HpaII. Only two probes (CPHO62 and -63) were found to differentiate reproducibly in two different genotypic backgrounds between nodular compact calli (NCC) and fast-growing calli (FGC), which generate 5% and 100% "mantled" plantlets, respectively. Comparative analyses were then conducted on DNA from inflorescences and leaves of normal and abnormal adult regenerants. With both probes, the observed methylation patterns were strongly clone-dependent and monomorphic with respect to the phenotype of the regenerants, except for the type-specific banding pattern obtained with the CPHO62 probe on material from the LMC3 clonal offspring. The results presented here mirror the higher difference in genomic DNA methylation observed between normal and abnormal embryogenic calli when compared to more differentiated plant material. Moreover, they reinforce the paramount interest of NCC and FGC callus lines as a material of choice in the search for early epigenetic markers of the "mantled" somaclonal variation. The potential use of methylation-sensitive RFLPs for the early detection of somaclonal variation at early stages of the micropropagation process is discussed.

Journal Article↗

PubMed2004

Novel human testis-specific histone H2B encoded by the interrupted gene on the X chromosome.

Testis-specific histones are synthesized and accumulated at specific stages of mammalian spermatogenesis. Their proposed functions range from facilitation of the replacement of somatic histones by protamines to epigenetic control of gene transcription. Several testis histone variants were characterized in mouse and rat; however, few are known in humans. Here we report the identification and characterization of a novel human histone 2B gene (TH2B-175) located at Xq22.2, which encodes a highly divergent H2B variant. The TH2B-175 gene contains two introns and is transcribed exclusively in testis, where the spliced polyadenylated mRNA was detected. Genomic PCR, Southern blot analysis, and BLAST-based searches indicate that TH2B-175 evolved in the primate lineage or has been lost in rodents. In transfected Chinese hamster cells, GFP-tagged TH2B-175 targeted to large fluorescent bodies that partially colocalize with the interstitial telomeric blocks. Therefore, TH2B-175 may have telomere-associated functions and participate in the telomere-binding complex in the human sperm [1].

Alternative Splicing↗

PubMedDate not supplied

Individual-specific 'fingerprints' of human DNA.

Simple tandem-repetitive regions of DNA (or 'minisatellites') which are dispersed in the human genome frequently show substantial length polymorphism arising from unequal exchanges which alter the number of short tandem repeats in a minisatellite. We have shown previously that the repeat elements in a subset of human minisatellites share a common 10-15-base-pair (bp) 'core' sequence which might act as a recombination signal in the generation of these hypervariable regions. A hybridization probe consisting of the core repeated in tandem can detect many highly polymorphic minisatellites simultaneously to provide a set of genetic markers of general use in human linkage analysis. We now show that other variant (core)n probes can detect additional sets of hypervariable minisatellites to produce somatically stable DNA 'fingerprints' which are completely specific to an individual (or to his or her identical twin) and can be applied directly to problems of human identification, including parenthood testing.

DNA Restriction Enzymes↗

PubMed1978

Argininosuccinic aciduria: assignment of the argininosuccinate lyase gene to the pter to q22 region of human chromosome 7 by bioautography.

Argininosuccinic aciduria, an autosomal recessive disorder of the urea cycle in humans, is associated with a deficiency of argininosuccinate lyase (ASL; L-argininosuccinate arginine-lyase, EC 4.3.2.1). ASL activity was visualized on gels after electrophoresis by a new method, termed bioautography. Bioautography involves the use of mutant bacteria to visualize the location of mammalian enzymes after zone electrophoresis. By this technique, human ASL migrated to a position different from mouse ASL, while a survey of mouse strains, tissues, and tissue culture cell extracts demonstrated the same electrophoretic form and no genetic variants of mouse ASL. Identifying human ASL, by bioautography in human-mouse somatic cell hybrids has made it possible to regionally locate the ASL gene on human chromosome 7. The human ASL phenotype segregated concordantly with the human enzyme beta-glucoronidase (GUS; beta-D-glucoronide glucuronosohydrolase, EC 3.2.1.31) in cell hybrids, but showed discordant segregation with 32 other enzyme markers representing 23 linkage groups. The gene for GUS has been assigned to chromosome 7 in humans, and cosegregation (synteny) of ASL and GUS demonstrates the assignment of ASL to chromosome 7. Regional location of ASL and GUS to the pter to q22 region of chromosome 7 was achieved in hybrids segregating a 7/9 translocation.

Amino Acid Metabolism, Inborn Errors↗