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PubMed2026

CHEK2 Germline Variants in Cancer Predisposition: Whole Genome Sequencing Results.

While pathogenic germline CHEK2 variants are known to increase cancer risk, there is currently insufficient evidence regarding the precise risk of developing malignant neoplasms associated with specific missense variants or variants of uncertain significance. As a result, no clear clinical guidelines exist regarding consultation, monitoring and specific treatment options for those patients. For the first time in Russia, clinical data and whole-genome sequencing (WGS) results were analyzed for 3150 patients with cancer and suspected hereditary cancer syndromes (HCS) and 5163 healthy individuals. This dataset formed the basis for assessing the role of germline CHEK2 variants in the development of different cancer types. The chromosomal coordinates and coding sequence coordinates are given in accordance with the GRCh38 (hg38) genome assembly and the NM_007194.4 transcript. Pathogenic (P) and likely pathogenic (LP) variants of CHEK2 significantly increased the risk of breast cancer (OR = 2.015 [95% CI: 1.27-3.21]; p = 0.0031), but the association with colorectal cancer was not statistically significant (OR = 1.354 [95% CI: 0.42-4.42]; p = 0.616). A moderate increase in cancer risk was identified for the c.1100del variant (OR = 2.263 [95% CI: 1.19-4.32]; p = 0.0132) and for the common P/LP variants c.1100del, c.444+1G>A and c.433C>T (OR = 2.219 [95% CI: 1.40-3.51]; p = 0.0007). Notably, our study confirmed that CHEK2 c.470T>C (p.Ile157Thr) is the most common variant in the patient group, identified in 3.8% of cases (120/3150), compared with 3.0% in the control group (155/5163). Although the association between the most common CHEK2 variant c.470T>C and cancer risk reached nominal statistical significance (OR = 1.279 [95% CI: 1.00-1.63]; p = 0.0463), the effect size was minimal, suggesting that the contribution of this variant to hereditary cancer risk in the Russian population is modest. Additional studies are required before this variant can be definitively excluded from clinical interpretation.

Humans↗
PubMed1987

Genetic variation between woodchuck populations with high and low prevalence rates of woodchuck hepatitis virus infection.

Woodchuck hepatitis virus (WHV) infection is known to be endemic in areas of the mid-Atlantic states but is apparently absent from populations in New York and much of New England. Blood samples of 40 woodchucks (Marmota monax) from New York and from Delaware were examined by starch gel electrophoresis, and 18 monomorphic and six polymorphic protein-coding genetic systems were identified. Mendelian inheritance of variants of the six polymorphic systems was confirmed in 52 laboratory offspring of the original samples. Average heterozygosity of 0.066 in New York woodchucks and 0.039 in Delaware woodchucks were high values for mammals, although similar to those of other sciurids. Significant heterogeneity between samples from New York and Delaware woodchucks was observed at two loci (peptidase with glycyl leucine-4 and phosphogluconate dehydrogenase), suggesting that these populations were genetically distinct. Whether there are genetically determined differences in response to WHV infection remains to be determined experimentally.

Alleles↗
PubMed2001

Bradykinin B(2) receptor endocytosis, recycling, and down-regulation assessed using green fluorescent protein conjugates.

Agonist-induced endocytosis and/or down-regulation have been evaluated using green fluorescent protein (GFP) conjugates of the rabbit bradykinin (BK) B2 receptor (B2R). COS-1 cells transiently transfected with vectors coding for either of two rabbit B2R fluorescent variants, B2R-GFP and B2R-GFP DeltaS/T (with previously identified Ser/Thr phosphorylation sites in the C-terminal tail mutated to Ala), exhibited specific and saturable binding (K(D) in the lower nM range). The acute addition of BK (10-100 nM) to HEK 293 cells stably expressing B2R-GFP in the presence of cycloheximide was rapidly followed by translocation of the surface receptors into the cells, with essentially complete recycling of the surface receptors in 1 to 3 h (confocal microscopy, cell fractionation). Adding captopril to inhibit angiotensin I-converting enzyme activity increased the half-life of BK in the culture medium (enzyme immunoassay) and, accordingly, promoted B2R-GFP internalization for at least 3 h. However, agonist-induced down-regulation was not observed under conditions optimal for endocytosis (microscopy, immunoblot using anti-GFP antibodies). In contrast, B2R-GFP was partially degraded following a short treatment of cells with trypsin. B2R-GFP internalized following agonist treatment was colocalized with fluorescent transferrin, supporting translocation of the receptor to recycling endosomes. B2R-GFP DeltaS/T failed to translocate into the cells following treatment with BK, but exhibited at baseline an altered subcellular distribution relative to B2R-GFP. The agonist BK promotes B(2)R receptor endocytosis followed by recycling to the cell surface, but does not promote receptor down-regulation in the heterologous system that we used here. Digestion initiated by extracellular proteases may be involved in pathological B2R down-regulation, as suggested by the simulation involving trypsin.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

[Genealogical research of hereditary nonpolyposis colorectal cancer].

OBJECTIVES To analyse the diagnosis and treatment of 24 hereditary nonpolyposis colorectal cancer (HNPCC) kindreds and report mismatch repair gene mutations. METHODS The diagnosis, treatment and follow-up of 24 HNPCC kindreds were reviewed retrospectively, cancer incidence and spectrum were recorded. Clinical characteristics and treatment were analyzed. Peripherial blood and genomic DNA were extracted from family members who had provided informed consent. PCR and SSCP were used to screen coding regions of the hMLH1 and hMSH2 genes. Variant bands were sequenced by 377 DNA sequencer after purification. RESULTS One hundred and 25 malignant neoplasms were diagnosed in 75 patients (multiple cancers in 24) with an average age of 51 years in 24 pedigrees. The onset of the disease occurred earlier than expected with the passing of each generation within large kindreds. The neoplasm mainly included colonic cancer (63 patients), rectal cancer(21), stomach cancer(13), endometric cancer(7), and esophageal cancers(6). 84% patients received radical operations. Of 64 patients with colorectal cancer 16 had metachronous colorectal cancer. 24% colorectal patients developed metachronous cancer within 10 years after initial operation and received re-operation. In 3 detected families with germline hMSH2 and hMLH1 mutations resulting in truncated protein, 12 carriers were found. CONCLUSIONS The main characteristics of hereditary nonpolyposis colorectal cancer include early onset and frequence of cancer; predominance of colorectal cancer, especially right-sided colonic cancer; frequency of multiple primary cancer, especially colorectal cancer; and age anticipation in large HNPCC pedigrees. Segmental resection of colorectal cancer is not suitable for colorectal cancer patient in HNPCC kindred. Intensive follow-up is important for all patients and possible gene carriers.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Perceptual strategies of isolation in obsessive-compulsive personality disorder.

Recent findings have shown that the Defense Mechanism Test, a serial tachistoscopic technique developed inside the percept-genetic frame of reference, discriminates neurotics from normals, neurotics from schizophrenic outpatients, and subjects with histrionic personality disorder from controls. The present research addresses another major class of Axis II pathology, comparing on the Defense Mechanism Test a group with a psychometric diagnosis of obsessive-compulsive personality disorder (n = 26) with a matched sample of noncompulsive controls. As predicted, several variants of isolation were significantly more characteristic of the compulsive group. Intellectualization, disappearance of the whole structure, whitening of the hero, and lack of recognition of the threat were the variants of isolation with the best discriminative properties. Codings of reaction formation were not linked with compulsive personality, which is congruent with the recent observation of their correspondence to the histrionic personality disorder. The findings are presented in the context of the percept-genetic literature on obsessive-compulsive defensive strategies.

Adult↗
PubMed1993

Oxidation, cross-linking, and insolubilization of recombinant tropoelastin by purified lysyl oxidase.

The use of recombinant human tropoelastin (rTE) and selected variants thereof as substrates for the assay of lysyl oxidase activity in vitro was explored. The possibility was also assessed that an insoluble elastin-like product could be generated from this elastin precursor in the absence of other macromolecules found associated with elastin in vivo. rTE was more efficiently oxidized by lysyl oxidase than the insoluble chick aorta elastin substrate conventionally used. Anionic amphiphilic elastin ligands strongly inhibited rTE oxidation consistent with the importance of electrostatic enzyme-substrate interactions previously noted with the insoluble elastin substrate. An rTE variant, rTE delta 26A, lacking the hydrophilic sequence coded by exon 26A, was a less effective substrate than rTE, largely due to an increase in Km, while the kinetic parameters for the oxidation of rTE delta 36, lacking the C-terminal polybasic sequence coded by exon 36, were quite similar to those for rTE. Incubation of rTE delta 26A with lysyl oxidase not only resulted in the generation of peptidyl alpha-aminoadipic-delta-semialdehyde and lysine-derived cross-linkages, but also yielded a product insoluble in hot 0.1 N NaOH, consistent with the properties of insoluble elastin. Thus, oxidation, cross-linking and insolubilization of elastin substrates by lysyl oxidase can occur in the absence of other macromolecules implicated as being involved in this process in vivo, although such macromolecules may be essential to obtain the proper alignment between tropoelastin units for specifically placed cross-linkages and optimally functional elastic fibers.

Amino Acid Sequence↗
PubMed1993

[Tay-Sachs disease].

GM2-gangliosidosis is a group of neurological disorders resulting from genetically defective catabolism, and consequent abnormal accumulation, of GM2-ganglioside. Three major types are distinguished: the B variant (Tay-Sachs disease), the O variant (Sandhoff disease), and the AB variant, caused by genetic abnormalities in the genes coding for the beta-hexosaminidase alpha- or beta-subunit, or the GM2-activator protein, respectively. A number of gene abnormalities responsible for Tay-Sachs disease have already been identified and the correlation between the beta-hexosaminidase alpha gene abnormality and the clinical phenotype has been explained in many cases. In the severest phenotype of Tay-Sachs disease (infantile form), mRNA of beta-hexosaminidase alpha subunit is not produced or is unstable such as in French Canadian patients or in Jewish patients with infantile Tay-Sachs disease, or the polypeptide does not have any catalytic activities because of the alteration of glycosylation such as the mutation of Glu482-to-Lys found in a Italian patient or the altered structure of polypeptide. The mutation identified in a large majority of the Japanese infantile Tay-Sachs disease patients, which is a G-to-T substitution at 3'-end of intron 5, generates a short mRNA with complete skipping of exon 6 and a polypeptide lacking 34 amino acids is generated but catalytically inactive. On the other hand, some active alpha beta dimers must be generated in patients with milder phenotypes of Tay-Sachs disease such as Gly269-to-Ser mutation in an adult form. Some of the mutations appear in high frequency among certain ethnic groups such as Ashkenazi Jewish patients and French Canadians.(ABSTRACT TRUNCATED AT 250 WORDS)

Age of Onset↗
PubMed1996

Emotion regulation in two-year-olds: strategies and emotional expression in four contexts.

A descriptive study of the modulation of negative emotion in the toddler period was conducted by examining expressions of negative emotion and the strategies used to reduce or change these expressions. 6 strategies were identified and evaluated in terms of their frequency of use in different situations, relations with emotional expressiveness, and cross-situational consistency. 37 2-year-olds were seen in 2 laboratory contexts (delay and separation) each with 2 variants. Emotion regulation strategies and emotional expressiveness were coded from videotapes of children's behavior in these 4 situations. Findings suggest that active engagement was most commonly used and most negatively associated with child distress. Use of strategies varied by context, and there was more cross-situational consistency in use of strategies that were more negatively or positively associated with distress within a given context than in use of particular strategies without consideration of their within-context significance.

Child Behavior↗
PubMed1996

[Typing of malignant mantle zone lymphomas].

Principles derived from a group of 46 ML of the mantle zone are presented: Mantle pattern of a ML and its cytological structure are mostly sufficient for positive basic diagnosis. Diffuse mantle zone ML need detection of BCL-1 and CD5 hyperexpression which are characteristic for small-cell and centrocytoid forms when compared with BCL-2 positive centrofollicular lymphomas. B monocytoid lymphomas from the parafollicular subgroup as well as plasmacytoid ML from the marginal subgroup retain faint BCL-1 positivity but lose CD5 positivity. That may results in attempt of problematic narrowing of mantle zone definition because of existence of the mixed cellularity forms of mantle zone ML. Nodular mantle zone ML are clinically recognized late and are unsensitive to treatment which is opposite to the original idea of their relative benignity. M-coding of mantle zone ML is very defective because the codes do not separate nodular (perifollicular) and diffuse variants.

Humans↗
PubMed1998

[Studying the possibility of respiratory immunization against tick-borne encephalitis].

There are known 3 likely mechanisms of virus conveyance into the central nervous system (CNS). These include hematogenic penetration, spread along the peripheral nerves, and the olfactory pathway which begins from the infected olfactory neuroepithelial cells. The possibility of viral spread into CNS via the olfactory pathway was shown for the representatives of togaviruses, herpesviruses, coronaviruses, rhabdoviruses, and for some others. This study suggests that the olfactory pathway of viral conveyance into CNS may be blocked by specific mucosal antibodies in the nasal mucosa. The recombinant TK- variant of WR vaccinia strain with inserted genes coding structural and nonstructural proteins of TBE virus is accumulated in the branches of the respiratory tract only while the parenteral vaccinia strain is detected in the brain regions, spleen, respiratory tract, and in blood. The protective activity of recombinant strain and inactivated TBE vaccine after mice immunization by escarification or intranasally, or subcutaneously was comparatively studied. The findings indicate that intranasal immunization by recombinant strain is the most protective against intraperitoneal challenge by TBE virus. The mucosal and humoral immune response that was induced by intranasal immunization seems to provide the highest levels of protection, which was experimentally observed.

Administration, Intranasal↗
PubMed1982

Structure of amplified normal and variant dihydrofolate reductase genes in mouse sarcoma S180 cells.

We constructed a gene library from a murine cell line with amplified dihydrofolate reductase (dhfr) genes by inserting random segments of DNA into lambda Ch4A. From this library, the dhfr gene and 30 kilobase pairs of surrounding DNA were cloned, and the restriction map was determined. All of the coding regions were sequenced and show that the gene spans a total of 31 kilobase pairs and has five intervening sequences in the coding portion of the gene. In addition, two classes of variant dhfr genes were found in the amplified line, which were amplified and present at levels of 10 to 30% of the normal dhfr genes. Numerous repeated sequences were located throughout the gene region, some of which share homology with previously defied families of repeats.

Animals↗
PubMed1985

[Molecular basis of the variability of epidemic strains of human influenza viruses].

The data from literature and authors own studies are reviewed on variability of human influenza viral strains, isolated during the same epidemic season in different periods of pandemic cycle. The data obtained indicate that variability of epidemic strains of human influenza virus deals with the genes coding for outer membrane proteins (hemagglutinin and neuraminidase) as well as nonglycosylated proteins. Circulation of a number of viral variants of the same serotype, differing in antigenic specificity of outer membrane proteins or in the genes coding for nonglycosylated proteins was registered during one and the same season of one epidemic. During circulation of viral variants of the same serotype recombination may take place. Heterogeneity of viral strains circulating during different epidemic seasons of the same pandemic cycle is different. The possible mechanisms of development of the new epidemic variants of human influenza virus are discussed.

Disease Outbreaks↗
PubMed1980

Identification of a trans-acting function regulation HLA-DR expression in a DR-negative B cell variant.

Somatic cell hybridizations were performed between an HLA-DR negative variant of a human B lymphoid cell line (B-LCL) and normal unrelated B-LCLs. The HLA-DR codes for polymorphic determinants on a heterodimeric cell surface lymphocyte differentiation glycoprotein. A variant subline which was selected in a single step from a diploid heterozygous DR-1 DR-3 B-LCL had lost expression of both DR-1 and DR-3 and the heretodimer; it has been described earlier. In a fusion with a DR-2 B-LCL, the hybrids expressed DR-2 and reexpressed the DR-1 and DR-3 alleles. Similar results were seen in a fusion with a different normal B-LCL. Hybrid clones from both fusions were tested with a large number of alloantisera and essentially all informative sera showed reexpression. The results show that (1) the variant did not arise by mutations in the structural genes for DR-1 and DR-3; (2) the normal cells are supplying a missing gene product needed for expression of DR; (3) this gene product is capable of acting in trans. Chromosome counts showed that the apparent recessiveness of the variant in the hybrids was not due to chromosomal segregation.

B-Lymphocytes↗
PubMed2006

A truncated isoform of TMEFF2 encodes a secreted protein in prostate cancer cells.

The transmembrane protein TMEFF2, also known as tomoregulin or TENB2, has been proposed as a potential immunotherapeutic target for the treatment of prostate cancer. Much attention has focused on its limited tissue distribution, with strong expression seen only in the brain and the prostate. Here we describe the identification of a novel splice variant of TMEFF2 expressed both in the normal prostate and in prostate cancer. This variant encodes an isoform of TMEFF2 that is truncated after the first four coding exons, eliminating both the EGF-like and the transmembrane domains. Fusion of GFP to this isoform demonstrated that this variant transcript produces a truncated TMEFF2 protein (TMEFF2-S). In contrast to full-length TMEFF2-GFP, the truncated TMEFF2-S-GFP fusion protein was enriched in cytosolic granules, showed no staining at the plasma membrane, and was secreted into the medium of transfected cells grown in tissue culture. These results indicate that a truncated isoform of TMEFF2 is expressed from this locus. This secreted form of TMEFF2 may functionally interact with full-length TMEFF2, or its binding partners, and may also influence current immune-based treatment strategies.

Alternative Splicing↗
PubMed2001

A novel proliferation-associated variant of CFR-1 defined by a human monoclonal antibody.

The germline coded human monoclonal IgM antibody 103/51 was isolated from a gastric carcinoma patient. This antibody binds to a 130-kd membrane molecule and has a mitotic effect on tumor cells in vitro. To characterize the target, we sequenced the protein and showed that the antibody binds to the cysteine-rich fibroblast growth factor receptor (CFR)-1, which is highly homologous to MG-160 and the E-selectin-ligand (ESL)-1. The epitope was determined by glycosidase-digestion experiments to be an N-linked carbohydrate side chain. Immunohistochemistry was used to investigate the tissue distribution of CFR-1. Different healthy tissues were tested and only the collecting tubes of the kidney, the Golgi apparatus, and the glomerular and fascicular zones of the adrenal gland stained positive. However, on malignant tissue the receptor is overexpressed in nearly all tested stomach cancers (12 of 15) and other tested carcinomas (13 of 15). Most interestingly, the receptor is also present in Helicobacter pylori gastritis and gastric dysplasia, but absent on uninflamed stomach mucosa. This restricted tissue pattern indicates that antibody 103/51 reacts with a membrane-bound variant of CFR-1, which is mainly expressed on transformed cells and precursor lesions and is essential for proliferation processes. The possible activity of antibody 103/51 as an activating ligand in these proliferative changes of gastric epithelial mucosa is discussed.

Adenocarcinoma↗
PubMed1983

Recombination between antibody heavy chain variable-region genes: evidence for gene conversion.

The murine hybridoma line B1-8.delta 1 secretes monoclonal IgD lambda 1 antibodies specific for the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP). The variable (V) region of these antibodies is defined by a characteristic pattern of idiotopes. A spontaneous V-region variant (B1-8.V1) with altered idiotope pattern was selected. The structural variation is confined to the V region of the heavy chain. It was shown previously that the variant V region is encoded by a gene that was generated by a crossover between the rearranged VDJ gene of the wild type (B1-8.delta 1) and a neighboring germ-line VH gene. In the present study the nucleotide sequence of coding and flanking regions of the VH gene expressed in variant B1-8.V1 was determined. Wild-type and variant VH genes differ at 15 positions in a region between leader sequence and codon 66. The sequence of the region carrying the substitutions is identical to the sequence of the corresponding region in a neighboring germ-line VH gene. This implies that the variant VH gene was generated by a mechanism of recombination more complicated than single crossover. Gene conversion as the mechanism of the recombination is discussed.

Animals↗
PubMed2003

Glutamate 346 of human Na+-H+ exchanger NHE1 is crucial for modulating both the affinity for Na+ and the interaction with amiloride derivatives.

A NHE1 variant that exhibits very high resistance to (3-methyl sulfonyl-4-piperidinobenzoyl) guanidine methane sulfonate (HOE694), a potent inhibitor of Na(+)-H(+) exchangers, was selected and characterized. Sequencing of the coding region corresponding to the N-terminal domain of this variant revealed the presence of only one mutation located within membrane-spanning segment 9 (M9). This base pair change replaces a glutamate (Glu) with an aspartate (Asp). We reproduced this amino acid change in wild-type NHE1 and found that this mutation alone is responsible for the huge decrease in sensitivity to the HOE694 compound and to ethylisopropylamiloride (EIPA). We found that the NHE1-Glu(346)Asp mutant was more than 2000-fold more resistant to HOE694 and up to 300-fold more resistant to EIPA than wild-type NHE1, with the size, rather than the charge, of the amino acid in position 346 having the greatest effect. Interestingly, its affinity for Na(+) was at least 4-fold lower than that of wild-type NHE1. Mutation of amino acids in the vicinity of Glu(346) did not change the sensitivity of mutated NHE1 proteins to inhibitors. We suggest there is a direct interaction of Glu(346) or involvement of Glu(346) in a coordination site with NHE inhibitors and with Na(+).

Amiloride↗
PubMed2005

High-throughput screening of enzyme libraries: thiolactonases evolved by fluorescence-activated sorting of single cells in emulsion compartments.

Single bacterial cells, each expressing a different library variant, were compartmentalized in aqueous droplets of water-in-oil (w/o) emulsions, thus maintaining a linkage between a plasmid-borne gene, the encoded enzyme variant, and the fluorescent product this enzyme may generate. Conversion into a double, water-in-oil-in-water (w/o/w) emulsion enabled the sorting of these compartments by FACS, as well as the isolation of living bacteria cells and their enzyme-coding genes. We demonstrate the directed evolution of new enzyme variants by screening >10(7) serum paraoxonase (PON1) mutants, to yield 100-fold improvements in thiolactonase activity. In vitro compartmentalization (IVC) of single cells, each carrying >10(4) enzyme molecules, in a volume of <10 femtoliter (fl), enabled detection and selection despite the fast, spontaneous hydrolysis of the substrate, the very low initial thiolactonase activity of PON1, and the use of difusable fluorescent products.

Aryldialkylphosphatase↗