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PubMed1983

Use of iron- or selenium-coupled monoclonal antibodies to cell-surface antigens as a positive selection system for cells.

A system which confers selective growth advantage to cells expressing particular surface proteins would be extremely desirable, for such a technique would allow the study of receptors using somatic cell genetic techniques such as DNA-mediated cell transformation and selection of over-producing cell variants. Polypeptides bound to surface receptor, and antibodies bound to surface antigens generally are taken up efficiently by cells by endocytotic mechanisms. Several investigators have accordingly developed useful techniques for selection against cells expressing surface receptors and antigens, using hormones and antibodies conjugated to toxins. We reasoned that conjugation of nutrients to antibodies or hormones conversely might permit a positive selective pressure to be applied in appropriately constituted medium. We report here that monoclonal antibodies to cell-surface antigens will indeed deliver nutritional iron and selenium to cultured cells in an antigen-specific manner.

Animals↗
PubMed2025

Cell-type-specific enrichment of somatic aneuploidy in the mammalian brain.

Somatic mutations alter the genomes of a subset of an individual's brain cells, impacting gene regulation and contributing to disease processes. Mosaic single-nucleotide variants have been characterized with single-cell resolution in the brain, but we have limited information about large-scale structural variation such as whole-chromosome duplication or loss. We used a dataset of over 415,000 single-cell DNA methylation and chromatin conformation profiles from the adult mouse brain to comprehensively identify and characterize aneuploid cells. Somatic trisomy events were strongly enriched on chromosome 16, which is syntenic with human chromosome 21. We also observed a specific enrichment of chromosome gain and loss events in specific cell types, including Pons neurons and oligodendrocyte precursor cells. Chromosome 16 trisomy occurred in multiple cell types and across brain regions, suggesting that nondisjunction is a recurrent feature of somatic structural variation in the brain.

Animals↗
PubMed2005

Desmoglein 2 is expressed abnormally rather than mutated in familial and sporadic gastric cancer.

Alterations of the cell adhesion molecule E-cadherin have been demonstrated in sporadic and hereditary gastric carcinomas. A cell adhesion molecule with functional similarity to E-cadherin is desmoglein 2 (Dsg2), a major component of the desmosomes. In this study, we investigated whether alterations of Dsg2 are involved in gastric carcinogenesis and whether germline mutations contribute to a genetic predisposition in familial gastric cancer patients with no germline mutations in the E-cadherin gene. Seventy-five formalin-fixed, paraffin-embedded tissues from 37 familial and 38 sporadic gastric carcinomas were analysed for Dsg2 expression by immunohistochemistry. DNA from 31 familial gastric cancer patients was analysed for germline mutations and five sporadic tumours were analysed for somatic mutations by DHPLC. Of the 75 tumours, 25 (33%) demonstrated abnormal (reduced and/or non-membrane-associated) Dsg2 expression. There was a trend towards more frequent abnormal expression in diffuse type (42%) than in intestinal type tumours (18%) (p = 0.066). One germline missense variant leading to a non-conservative amino acid change (c. 2810 C > A, Thr 937 Asn) was found in a familial gastric cancer patient with a diffuse type tumour. No somatic mutations were identified. The observed abnormal expression of Dsg2 protein suggests that this molecule is involved in the carcinogenesis of a subset of gastric carcinomas, in particular of the diffuse type. Somatic mutations in the gene do not seem to be a very frequent inactivation event and the finding of no clear pathogenic germline mutation rules out Dsg2 as a major gastric cancer predisposition gene.

Adult↗
PubMed1993

Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis.

Spontaneous errors in DNA replication have been suggested to play a significant role in neoplastic transformation and to explain the chromosomal alterations seen in cancer cells. A defective replication factor could increase the mutation rate in clonal variants arising during tumour progression, but despite intensive efforts, increases in tumour cell mutation rates have not been unambiguously shown. Here we use an unbiased genomic fingerprinting technique to show that 12 per cent of colorectal carcinomas carry somatic deletions in poly(dA.dT) sequences and other simple repeats. We estimate that cells from these tumours can carry more than 100,000 such mutations. Only tumours with affected poly(dA.dT) sequences carry mutations in the other simple repeats examined, and such mutations can be found in all neoplastic regions of multiple tumours from the same patient, including adenomas. Tumours with these mutations show distinctive genotypic and phenotypic features. We conclude that these mutations reflect a previously undescribed form of carcinogenesis in the colon (predisposition to which may be inherited) mediated by a mutation in a DNA replication factor resulting in reduced fidelity for replication or repair (a 'mutator mutation').

Adult↗
PubMed1987

Variation in milk protein concentrations associated with genetic polymorphism and environmental factors.

Concentrations of alpha s-casein, beta-casein, kappa-casein, beta-lactoglobulin, alpha-lactalbumin, serum albumin, and immunoglobulin in milk from 1888 Holstein cows were determined monthly over the lactation period. Cows were phenotyped for genetic variants of alpha s1-casein, beta-casein, kappa-casein, and beta-lactoglobulin. Least squares analyses showed variations in individual proteins due to parity number, month of test, stage of lactation, somatic cell count, fat content, milk yield, and phenotypes of cows for milk proteins. beta-Casein declined and serum proteins increased with advancing age of cows. Concentration of individual proteins decreased during the first 2 to 3 mo in lactation and then increased as lactation progressed. alpha s1-Casein variants significantly affected concentrations of alpha s-casein (BC greater than BB greater than AB) and beta-lactoglobulin (AB greater than BB greater than BC). Variant B for beta-casein is associated with lower alpha s-casein, beta-lactoglobulin, immunoglobulins, and higher beta-casein and alpha-lactalbumin concentrations than variant A1, A2, or A3. Milk from BB kappa-casein, and BB beta-lactoglobulin cows contained more alpha s-casein, kappa-casein, and less beta-lactoglobulin than milk from AA cows for the two proteins. Concentrations of all proteins were negatively correlated with milk production. Increased somatic cell counts were associated with lower beta-casein and higher concentrations of other proteins. Fat content of milk was positively correlated with the three casein fractions and beta-lactoglobulin.

Animals↗
PubMed1999

Rapsyn variants in ciliary ganglia and their possible effects on clustering of nicotinic receptors.

Nicotinic acetylcholine receptors (nAChRs) containing the alpha7 gene product can influence a range of cellular events in neurons, depending on receptor location. On chick ciliary neurons, the receptors are concentrated on somatic spines, but little is known about mechanisms responsible for sequestering them there. Rapsyn is a 43-kDa protein essential for clustering nicotinic receptors at the vertebrate neuromuscular junction. RT-PCR confirmed previous studies showing that the chick ciliary ganglion expresses rapsyn transcripts, including several splice variants lacking part or all of exon 2. Heterologous expression of rapsyn constructs, together with nicotinic receptor constructs, shows that chicken full-length rapsyn can induce clustering of both muscle and neuronal nicotinic receptors. Splice variants lacking one or both leucine zipper motifs of exon 2 are unable to cluster the receptors, though, like full-length rapsyn, they cluster themselves. Immunological analysis demonstrates the presence of full-length rapsyn in chick muscle extracts but fails to detect either full-length or splice-variant versions of rapsyn at significant levels in ganglion extracts. The results suggest that rapsyn does not cluster alpha7-nAChRs on ciliary neurons in any way similar to that of receptors at the neuromuscular junction where rapsyn and the receptors are present in approximately equimolar amounts.

Alternative Splicing↗
PubMed2003

Absence of somatic ATM missense mutations in 58 mammary carcinomas.

Accumulating evidence indicates that germline missense mutations in the ATM gene predispose to breast cancer. To investigate the potential role of somatic ATM mutations in the tumorigenesis of breast cancer, the ATM gene was scanned in 58 mammary carcinomas using DOVAM-S (detection of virtually all mutations-SSCP [single-strand conformation polymorphism]), a robotically enhanced, highly redundant form of SSCP that detects virtually all mutations. A total of 1.65 megabases of tumor DNA sequence was scanned and 16 structural variants were identified, including one novel nonsense mutation, four novel missense mutations, and a common missense change in African-Americans. Sequencing from microdissected normal cells reveals that all variants were present in the germline. Thus, the ATM gene may be similar to the BRCA1/BRCA2 genes in that germline mutations are important in cancer predisposition, but somatic mutations are seldom present in tumors. Loss of heterozygosity (LOH) is common in these tumors, but ATM missense mutations occur with similar frequencies when LOH is present or absent (P=0.73). If germline ATM missense mutations predispose to breast cancer, the unmasking of a recessive missense allele by LOH does not seem to be a critical step in breast neoplasia.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

Comparative genomic hybridization and BUB1B mutation analyses in childhood cancers associated with mosaic variegated aneuploidy syndrome.

We previously demonstrated that constitutional BUB1B mutations cause mosaic variegated aneuploidy, a condition characterized by constitutional aneuploidies and childhood cancer predisposition. To further investigate the role of BUB1B in cancer predisposition we performed comparative genomic hybridization analysis in an embryonal rhabdomyosarcoma from an MVA case with biallelic BUB1B mutations, revealing aneuploidies typical of sporadic E-RMS, with gain of chromosomes 3, 8, 13 and loss of chromosomes 9, 14, X. To investigate whether somatic BUB1B mutations occur in sporadic childhood cancers we screened 30 Wilms tumours, 10 acute lymphoblastic leukemias, nine rhabdomyosarcomas and 11 rhabdomyosarcoma cell lines for BUB1B mutations. We identified seven exonic and six intronic variants. Six of the exonic variants were synonymous and one resulted in a non-synonymous conservative missense alteration that was also present in a control. These data suggest that the genetic progression in rhabdomyosarcoma from MVA and non-MVA cases may be similar, but that somatic BUB1B mutations are unlikely to be common in sporadic childhood cancers known to be associated with MVA.

Aneuploidy↗
PubMed2002

Somatic glypican 3 (GPC3) mutations in Wilms' tumour.

Tumour and normal tissue from 41 male cases of Wilms' tumour were screened to determine the presence of sequence variants in the glypican 3 (GPC3) gene. Two non-conservative single base changes were present in tumour tissue only. These findings imply a possible role for GPC3 in Wilms' tumour development.

DNA Primers↗
PubMed1995

Germline mosaicism for an alanine to valine substitution at residue beta 140 in hemoglobin Puttelange, a new variant with high oxygen affinity.

Hb Puttelange [beta 140(H18)Ala-->Val] was found as a de novo mutation in two siblings of a French family suffering from polycythemia. Both parents were phenotypically normal and exclusion of paternity has been ruled out by the study of several polymorphic markers located on different chromosomes. The structural modification of Hb Puttelange was established by reversed-phase HPLC analysis of the tryptic digest of the abnormal chain. The amino acid composition of an abnormal beta T14 peptide revealed that one of the four residues of Ala was replaced by a Val. Tandem mass spectrometry demonstrated that the substitution concerned position beta 140 (H18). This hemoglobin displays an increased oxygen affinity that is responsible for the polycythemia. De novo mutations, as demonstrated again in the case of this variant, have the highest probabilities of detection when they lead to pathological manifestations. They may result either from a somatic mutation in a very early stage of the embryological development of the propositus or may have a parental origin with occurrence of a germline mosaicism. The study of the beta-globin gene indicated that this case of Hb Puttelange probably arose from a mutation affecting a part of the germline of the father, therefore leading to a true recurrence risk.

Adult↗
PubMed1992

Differential subcellular distribution of the alpha 6 subunit versus the alpha 1 and beta 2/3 subunits of the GABAA/benzodiazepine receptor complex in granule cells of the cerebellar cortex.

The distribution of the alpha 6 subunit of the GABAA receptor has been established in rat cerebellum and compared to the distribution of the alpha 1 (cat) and the beta 2/3 (rat, cat) subunits, using immunocytochemistry. The synapses established by Golgi cell terminals on the dendrites of granule cells were immunoreactive for the alpha 6, alpha 1 and beta 2/3 subunits in virtually all glomeruli, indicating that two variants (alpha 1 and alpha 6) of the same subunit are co-localized at the same synapses. The somatic membranes of the granule cells, which receive no synapses, were immunopositive for the alpha 1 and beta 2/3 subunits, but not for the alpha 6 subunit. Thus, the alpha 1 and the beta 2/3 subunits are located at both synaptic and extrasynaptic sites, but the alpha 6 subunit is detectable only at synaptic sites.

Animals↗
PubMed1982

Clonal interaction in tumours.

The development of cancer is contingent on the emergence of at least one clone of transformed cells. One method used to investigate whether human tumours are monoclonal depends on the mosaicism in the normal tissues of women heterozygous for the two forms of the enzyme glucose-6-phosphate dehydrogenase (G-6-PD). This mosaicism results from the inactivation of one X chromosome in all somatic cells and should not exist in a monoclonal population. Following the discovery in feral mice of an electrophoretic variant (A) of the X-coded enzyme phosphoglycerate kinase (PGK-1) which differs from the form (B) found in common laboratory mouse strains it was reported that fibrosarcomas induced chemically in hybrids of feral and laboratory-bred mice expressed both enzyme phenotypes, but the conclusion that both were expressed by neoplastic cells was based solely on morphological evidence. The development of histocompatible substrains of mice homozygous for one or other alloenzyme has made it possible to study the clonal composition of tumours under experimental conditions in which the neoplastic status of subpopulations of cells can be verified by transplantation. The experiments we now report, while confirming that murine fibrosarcomas are often pleoclonal, show that the clonal composition may change markedly during tissue culture and on transplantation to congenic hosts. These changes presumably reflect changes in the growth kinetics of differentiating subpopulations of the tumour. Cloned sublines are less readily transplantable than uncloned tumour cell populations, and some sublines are less readily transplantable than others; this suggests that sublines resistant to a host's attack are selected on transplantation or that some sublines require the cooperation of others to survive. We postulate that changes in clonal composition occur also during tumour development, metastasis and recurrence.

Animals↗
PubMed2005

Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase.

X inactivation involves the stable silencing of one of the two X chromosomes in XX female mammals. Initiation of this process occurs during early development and involves Xist (X-inactive-specific transcript) RNA coating and the recruitment of Polycomb repressive complex (PRC) 2 and PRC1 proteins. This recruitment results in an inactive state that is initially labile but is further locked in by epigenetic marks such as DNA methylation, histone hypoacetylation, and MACROH2A deposition. Here, we report that the E3 ubiquitin ligase consisting of SPOP and CULLIN3 is able to ubiquitinate the Polycomb group protein BMI1 and the variant histone MACROH2A. We find that in addition to MACROH2A, PRC1 is recruited to the inactivated X chromosome in somatic cells in a highly dynamic, cell cycle-regulated manner. Importantly, RNAi-mediated knock-down of CULLIN3 or SPOP results in loss of MACROH2A1 from the inactivated X chromosome (Xi), leading to reactivation of the Xi in the presence of inhibitors of DNA methylation and histone deacetylation. Likewise, Xi reactivation is also seen on MacroH2A1 RNAi under these conditions. Hence, we propose that the PRC1 complex is involved in the maintenance of X chromosome inactivation in somatic cells. We further demonstrate that MACROH2A1 deposition is regulated by the CULLIN3/SPOP ligase complex and is actively involved in stable X inactivation, likely through the formation of an additional layer of epigenetic silencing.

Blotting, Western↗
PubMed1983

Serologic and functional characterization of a panel of antigen-presenting cell lines expressing mutant I-A class II molecules.

An improved method is described for selecting mutant cells with an altered pattern of Ia antigenic determinants and antigen-presenting properties from an homogeneous population of functional antigen-presenting cells (APC). The APC line used, TA3, was a somatic cell hybrid obtained by fusing normal heterozygous H-2a/d B cells with a drug-marked variant of a BALB/c B lymphoma line. Two phenotypic groups of mutants were obtained by this method. Serologic analysis with a panel of anti-I-Ak monoclonal antibodies suggested that the change in the first group of mutants (type A mutants) involved the alteration of a portion of one epitope of the I-Ak molecule while in the second group of mutants (type B), an alteration of a different Ia epitope group had occurred. Functional studies using a panel of cloned antigen-specific and autoreactive T cell hybridomas demonstrated that the loss of a limited number of I-Ak determinants in the type A mutants correlated with the loss of some but not all I-Ak-encoded restriction elements, while the type B mutation(s) resulted in the ablation of all I-Ak-restricted APC functions tested. These mutations may occur in the region of the Ia molecule that interacts with the T cell receptor (the histope) or in a postulated region that interacts with antigen (the desetope). The finding that both type A and B mutations lead to loss in the capacity to be corecognized with many different antigens by I-Ak-restricted T cell hybridomas suggests that the Ia molecule may possess very few distinct histotopes and/or desetopes or that the tertiary structure of the Ia molecule is crucial in the formation of these sites. Alternatively, the mutations, particularly the type B mutations, may have led to the failure of expression of an entire alpha or beta chain.

Animals↗
PubMed1984

A small plasmid in Shigella dysenteriae 1 specifies one or more functions essential for O antigen production and bacterial virulence.

The role of plasmids in the virulence of Shigella dysenteriae 1 W30864, which contains at least five species, was investigated. By means of a standard plasmid-curing procedure, that is, bacterial cultivation at an elevated temperature, five virulence-deficient derivatives were obtained. One of these lacked a small, 6-megadalton plasmid, designated pHW400, exhibited reduced invasiveness for HeLa cells, and failed to produce the somatic antigen. Transposon tagging of the pHW400 plasmid to produce pHW401 and the transfer of this derivative into a variant of strain W30864 lacking pHW400 confirmed the conclusion that the pHW400 plasmid encodes one or more functions involved in O antigen (lipopolysaccharide) biosynthesis and bacterial virulence. A plasmid of similar size was detected in all of the three other strains of S. dysenteriae 1 examined.

Antigens, Bacterial↗
PubMed2005

Marble brain disease in two Saudi Arabian siblings.

Marble brain disease, also known as Guibaud-Vainsel syndrome, is a syndrome consisting primarily of renal tubular acidosis, cerebral calcification and osteopetrosis. The majority of reports originate from the Middle East. It is an autosomal recessive condition owing to carbonic anhydrase type II deficiency in renal and brain cells with a variant form of osteopetrosis. We report two siblings with this condition from Saudi Arabia. Both cases improved in both somatic growth and mental development after commencing treatment for renal tubular acidosis in the form of alkaline therapy and potassium supplementation.

Acidosis, Renal Tubular↗
PubMed1996

p53 is frequently mutated in Barrett's metaplasia of the intestinal type.

Barrett's Esophagus (BE) is a complication of gastroesophageal reflux in which the normal squamous epithelium of the lower esophagus is replaced by metaplastic tissue. The clinical significance of this condition is the associated predisposition to adenocarcinomas (ADCs). Three types of BE have been characterized: the gastric fundic (F) type, the gastric cardial (C) type, and the intestinal (I) type. The latter is the most closely associated with the development of ADCs; the causes of this bias remain unknown. To determine whether p53 and/or K-ras gene alterations (a) are present in preneoplastic lesions and (b) are associated with a specific histotype, we performed PCR-based denaturing gradient gel electrophoresis (DGGE) analysis of exon 1 (codons 12-13) of K-ras gene and of exons 5-8 of the p53 gene in biopsies obtained from 30 patients with BE of the I type (9 patients), combined I type (I + C +/- F; 10 patients) and non-I type (C, F, or C + F; 11 patients). None of the cases under study revealed K-ras mutations, whereas biopsies from 12 patients showed at least one p53 DGGE variant. Four patients showed the exact same variants in leukocytes also (polymorphisms), whereas eight cases revealed specific DGGE variants only in biopsies. The molecular characterization of these variants revealed that four of them showed a single base pair substitution, and four showed multiple mutations. Of 17 somatic mutations, all but 1 were base pair substitutions located mainly in exons 7 and 8. The majority of these mutations were GC targeted (13 of 16; 81%), 54% (7 of 13) of which were transitions occurring at CpG sites. All somatic mutations were found in BE with at least one I component. The association with the histotype was statistically significant (P < 0.03; pure I type versus non-I type; P < 0.04, combined I type versus non-I type; Fisher's exact test). Loss of heterozygosity in the vicinity of the p53 locus was evaluated by PCR using a highly polymorphic variable number of tandem repeats marker on 25 out of 30 cases. Ninety-two % of the cases analyzed were informative, and none of them showed LOH. In conclusion, we showed that p53 mutations are frequently observed in specimens from BE patients of the I-type, whereas no involvement of K-ras (exon 1) mutational activation was observed. In light of the key roles that the p53 protein plays in controlling cell cycle and cell diploidy, this result may suggest why this type of metaplasia is the most closely associated to the development of ADCs.

Adult↗
PubMed2002

Use of somatic cells from goat milk for dynamic studies of gene expression in the mammary gland.

Somatic cells are present in the milk throughout lactation and consist of leukocytes and epithelial cells exfoliated from the mammary epithelium. Our objective was to determine the efficacy of using somatic cells from goat milk for dynamic studies of gene expression in the mammary gland. Over a 4-wk interval, cells were isolated from daily morning milk samples and samples taken 30 min after milking. They were characterized by direct cell counts and by flow cytometry analysis after immunostaining with antibodies directed against cytokeratin and CD45, a common leukocyte antigen. Epithelial cell counts within the morning milk ranged from 15 to 45% of total milk somatic cells. After-milking samples contained twice as many cells as did morning milk samples. The RNA was extracted from the somatic cells of both types of milk samples with equivalent efficiency (a mean of 1.2 microg RNA/mL of milk). Four mRNA variants of the alpha-S1 casein gene were detected by Northern blot analysis and the amount of each mRNA in milk cells was related to protein concentration in milk. The comparison between mRNA from the mammary gland and from congruently collected milk cells showed that relative amounts of mRNA for each milk-protein (alpha-S1 and kappa-casein and alactalbumin) were conserved. In a third experiment, daily milk cell RNA preparations were extracted to assess the effect of growth hormone (GH) on mammary gene expression; four goats were separated into two groups in order to perform a switch-back design consisting of three treatment weeks: Control, GH-Control or GH-Control-GH. In this study, treatment of goats with GH increased milk yields by 5%. Throughout the control and GH treatments, the expression of the three milk-protein genes studied were highly and significantly correlated (r = 0.949 and r = 0.958, P < 0.001 for, respectively, alpha-S1 and kappa-casein and for alpha-S1 casein and alpha-lactalbumin). During GH treatment, the three milk-protein mRNA abundances increased with the same pattern. In conclusion, the opportunity to use milk somatic cells for RNA preparation and analysis provides a significant improvement over the use of biopsy samples in assessing gene activity in the mammary gland and allows easy and repetitive sampling without damaging mammary tissue. Furthermore, we propose that this method could be used to investigate the transcriptional status of the mammary gland of an animal in relation to its genotype, nutritional and pathologic status, and under influence by hormonal factors.

Animals↗