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PubMed1997

Increased lymphomagenicity and restored disease specificity of AML1 site (core) mutant SL3-3 murine leukemia virus by a second-site enhancer variant evolved in vivo.

SL3-3 is a highly T-lymphomagenic murine retrovirus. The major genetic determinant of disease is the transcriptional enhancer, which consists of a repeated region with densely packed binding sites for several transcription factors, including AML1 (also known as core binding factor and polyoma enhancer-binding protein 2) and nuclear factor 1 (NF1). Previously, we examined the enhancer structure of proviruses from murine tumors induced by SL3-3 with mutated AML1 (core) sites and found a few cases of second-site alterations. These consisted of deletions involving the NF1 sites and alterations in overall number of repeat elements, and they conferred increased enhancer strength in transient transcription assays. We have now tested the pathogenicity of a virus harboring one such second-site variant enhancer in inbred NMRI mice. It induced lymphomas with a 100% incidence and a significantly shorter latency than the AML1 mutant it evolved from. The enhancer structure thus represents the selection for a more tumorigenic virus variant during the pathogenic process. Sequencing of provirus from the induced tumors showed the new enhancer variant to be genetically stable. Also, Southern blotting showed that the tumors induced by the variant were T-cell lymphomas, as were the wild-type-induced lymphomas. In contrast, tumors induced by the original core/AML1 site I-II mutant appeared to be of non-T-cell origin and several proviral genomes with altered enhancer regions could be found in the tumors. Moreover, reporter constructs with the new tumor-derived variant could not be transactivated by AML1 in cotransfection experiments as could the wild type. These results emphasize the importance of both core/AML1 site I and site II for the pathogenic potential of SL3-3 and at the same time show that second-site alterations can form a viral variant with a substantial pathogenic potential although both AML1 sites I and II are nonfunctional.

Animals↗
PubMed2007

Vaccination and the dynamics of immune evasion.

Vaccines exert strong selective pressures on pathogens, favouring the spread of antigenic variants. We propose a simple mathematical model to investigate the dynamics of a novel pathogenic strain that emerges in a population where a previous strain is maintained at low endemic level by a vaccine. We compare three methods to assess the ability of the novel strain to invade and persist: algebraic rate of invasion; deterministic dynamics; and stochastic dynamics. These three techniques provide complementary predictions on the fate of the system. In particular, we emphasize the importance of stochastic simulations, which account for the possibility of extinctions of either strain. More specifically, our model suggests that the probability of persistence of an invasive strain (i) can be minimized for intermediate levels of vaccine cross-protection (i.e. immune protection against the novel strain) and (ii) is lower if cross-immunity acts through a reduced infectious period rather than through reduced susceptibility.

Antigenic Variation↗
PubMed1996

Whole genome analysis of hepatitis B virus from four cases of fulminant hepatitis: genetic variability and its potential role in disease pathogenicity.

The precore stop-codon variant of hepatitis B virus (HBV) has been associated with fulminant hepatitis but is also found in patients with persistent infection and chronic hepatitis. We have examined the possibility that the severe outcome of infection in patients with fulminant disease may be a result of additional genomic variation. We sequenced the entire HBV genome from three patients of Greek and one patient of Chinese origin with fulminant hepatitis, and from two patients with hepatitis B e antigen (HBeAg) positive chronic infection from the same regions, using direct sequencing of amplified viral DNA. Three of the fulminant cases were infected with the precore stop-codon variant HBeAg negative) and the fourth with the wild-type (HBeAg) positive virus. We compared sequences from our four fulminant isolates, and an additional fulminant isolate reported by others, with HBeAg positive carriers from the same regions and 12 published HBV genomes. There was a higher number of nucleotide and amino-acid substitutions throughout the HBV genome in the precore variant fulminant sequences than in the wild type. A cluster of mutations previously identified in the X region (126-132) in sequences reported in Japanese patients and encompassing the Enhancer II-Core Promoter region (1751-1768), were not found in our patients. We conclude that although there are no changes common to all sequences of HBV isolates from fulminant cases, some of these changes are in recognized cis-acting regulatory elements, whilst others are in the immediate vicinity of such elements. The effect of these mutations on viral genome transcription must now be determined.

Amino Acid Sequence↗
PubMed1993

Autoantigen inhibits apoptosis of a human B cell leukemia that produces pathogenic rheumatoid factor.

We studied a variant CD5- B cell chronic lymphocytic leukemia (CLL) cell population that produces pathologic IgM kappa rheumatoid factor autoantibodies. In contrast to common CD5+ B cell CLL, this variant leukemia cell population displays intraclonal diversity in its expressed Ig V genes, similar to that noted for follicular B cell non-Hodgkin's lymphomas. Also, in contrast to common B cell CLL, these leukemia cells rapidly undergo cell death hours after being placed in tissue culture. We find that addition of Ag (aggregated human IgG) enhances significantly the survival of these cells in vitro. Leukemia cell survival also could be enhanced by exogenous IFN-gamma or anti-CD40 presented on Fc gamma RII (CDw32)-expressing L cells, but not by exogenous IL-4, IL-6, or monomeric human IgG. We find that Ag acts directly on the leukemia B cells to inhibit apoptosis. This effect could be mimicked by cross-linking the leukemia cells' surface IgM receptors with immobilized murine mAb specific for human Ig mu-chains, but not by immobilized mAb of irrelevant specificity. In contrast to most follicular NHL, this leukemia B cell population does not have evidence of bcl-2 gene rearrangement. Also, in contrast to non-Hodgkin's lymphomas and most B cell CLL, these cells do not express detectable amounts of bcl-2. Finally, although capable of inhibiting apoptosis, surface Ig receptor cross-linking does not induce expression of bcl-2 in these variant leukemia cells. We hypothesize that the lack of bcl-2 expression may render these leukemia cells particularly dependent upon the survival signal(s) derived from surface Ig receptor cross-linking. This state may represent an early stage in leukemia/lymphomagenesis, possibly accounting for the intraclonal diversity observed in the Ig V genes expressed by certain CD5- B cell leukemias and lymphomas.

Antigens, CD↗
PubMedDate not supplied

Assessment of pathogenicity criteria for constitutional missense mutations of the hereditary nonpolyposis colorectal cancer genes MLH1 and MSH2.

To determine the role played by MLH1 and MSH2 missense variants in cancer susceptibility, we have investigated the following genetic and biological characteristics associated with six MLH1 and four MSH2 missense changes identified in Italian hereditary nonpolyposis colorectal cancer (HNPCC) families: co-segregation with disease phenotype and/or bonafide pathogenetic mutations; presence of the variant in healthy control subjects; evolutionary conservation of the involved aminoacid and type of aminoacid change; and presence/absence of microsatellite instability (MSI) in tumour DNA. Overall, nine variants did not fulfil > or = 2 pathogenicity criteria. MSI was investigated in tumour samples from carriers of nine different missense mutations. Only 3/9 variants were associated with MSI in tumour DNA. In addition, four variants were not present in affected pedigree members, and five variants were observed in the control population. Based upon these results, we conclude that most MLH1 and MSH2 missense changes are unlikely to act as major causative factors in colorectal cancer susceptibility and development.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Structure-function relationships among wild-type variants of Staphylococcus aureus beta-lactamase: importance of amino acids 128 and 216.

beta-Lactamases inactivate penicillin and cephalosporin antibiotics by hydrolysis of the beta-lactam ring and are an important mechanism of resistance for many bacterial pathogens. Four wild-type variants of Staphylococcus aureus beta-lactamase, designated A, B, C, and D, have been identified. Although distinguishable kinetically, they differ in primary structure by only a few amino acids. Using the reported sequences of the A, C, and D enzymes along with crystallographic data about the structure of the type A enzyme to identify amino acid differences located close to the active site, we hypothesized that these differences might explain the kinetic heterogeneity of the wild-type beta-lactamases. To test this hypothesis, genes encoding the type A, C, and D beta-lactamases were modified by site-directed mutagenesis, yielding mutant enzymes with single amino acid substitutions. The substitution of asparagine for serine at residue 216 of type A beta-lactamase resulted in a kinetic profile indistinguishable from that of type C beta-lactamase, whereas the substitution of serine for asparagine at the same site in the type C enzyme produced a kinetic type A mutant. Similar bidirectional substitutions identified the threonine-to-alanine difference at residue 128 as being responsible for the kinetic differences between the type A and D enzymes. Neither residue 216 nor 128 has previously been shown to be kinetically important among serine-active-site beta-lactamases.

Alanine↗
PubMed2006

The impact on coronary artery disease of common polymorphisms known to modulate responses to pathogens.

There are two distinct models to explain how genetic variants contributing to cardiovascular disease may have arisen. Firstly, variants may result from random, initially neutral, mutations whose effects are largely revealed in post-reproductive individuals in industrialized societies. Alternatively, the introduced variants may confer an adaptive advantage in certain circumstances. Resistance to pathogens is one of the strongest selection pressures on human proteins. To determine whether this evolutionary pressure has made a large contribution to heart disease we tested whether seventeen polymorphisms in fourteen innate-immunity genes, with documented evidence of modulating response to pathogens, had an impact on heart disease. Genotyping was performed in 1,598 CAD subjects (ACS or stable angina) and 332 controls. The TLR4 399Ile allele had the greatest impact on ACS risk (uncorrected p = 0.006); however there was no evidence overall that the resistance alleles cumulatively influenced the risk of ACS compared to controls or stable angina patients (p = 0.12, and p = 0.40, respectively). We did note a significant interaction between age at onset of disease and combined resistance allele carriership when the ACS and non-thrombotic, stable angina groups were compared (p = 0.04, 16 d.f.). This suggests that innate immunity factors could have a greater impact on thrombus formation among younger CAD patients.

Acute Disease↗
PubMed1997

PilC of Neisseria meningitidis is involved in class II pilus formation and restores pilus assembly, natural transformation competence and adherence to epithelial cells in PilC-deficient gonococci.

Type 4 pili produced by the pathogenic Neisseria species constitute primary determinants for the adherence to host tissues. In addition to the major pilin subunit (PilE), neisserial pili contain the variable PilC proteins represented by two variant gene copies in most pathogenic Neisseria isolates. Based upon structural differences in the conserved regions of PilE, two pilus classes can be distinguished in Neisseria meningitidis. For class I pili found in both Neisseria gonorrhoeae and N. meningitidis, PilC proteins have been implicated in pilus assembly, natural transformation competence and adherence to epithelial cells. In this study, we used primers specific for the pilC2 gene of N.gonorrhoeae strain MS11 to amplify, by the polymerase chain reaction, and clone a homologous pilC gene from N. meningitidis strain A1493 which produces class II pili. This gene was sequenced and the deduced amino acid sequence showed 75.4% and 73.8% identity with the gonococcal PilC1 and PilC2, respectively. These values match the identity value of 74.1% calculated for the two N. gonorrhoeae MS11 PilC proteins, indicating a horizontal relationship between the N. gonorrhoeae and N. meningitidis pilC genes. We provide evidence that PilC functions in meningococcal class II pilus assembly and adherence. Furthermore, expression of the cloned N. meningitidis pilC gene in a gonococcal pilC1,2 mutant restores pilus assembly, adherence to ME-180 epithelial cells, and transformation competence to the wild-type level. Thus, PilC proteins exhibit indistinguishable functions in the context of class I and class II pili.

Amino Acid Sequence↗
PubMed1986

Studies on the genetic determinants of influenza virus pathogenicity for mice with the use of reassortants between mouse-adapted and non-adapted variants of the same virus strain.

The original influenza virus strain A/USSR/90/77 (H 1 N 1) and its mouse-adapted variant, differing in their reactivity with anti-hemagglutinin monoclonal antibodies HC 22 and HC 124, were crossed in MDCK cells and in chicken embryos, and 21 clones were isolated by non-selective random cloning. In all the clones the virulence for mice was found to be linked to the antigenic specificity of hemagglutinin (HA). An independent marker, formation of filamentous forms, was reassorted with an expected frequency. In the crosses between UV-irradiated mouse-adapted variant and live non-adapted strain, with selection of clones by a mixture of monoclonal antibodies discriminating between HA of the two variants, virulence also was linked to HA gene. On the contrary, in the experiments with A/Aichi/2/68 (H 3 N 2) strain and its mouse-adapted highly virulent variant these two characteristics--virulence and HA antigenic specificity--could be dissociated. A pathogenic clone having HA of the non-adapted strain was readily obtained; its virulence, however, was weaker than that of the mouse-adapted parent. In the inter-subtypic crosses between A/USSR/90/77 and A/Aichi/2/68 the transfer of the HA gene of the mouse-adapted A/Aichi/2/68 did not confer virulence to the reassortant. The results are discussed in terms of the genetic basis of virulence acquired in the course of influenza virus adaptation to a new host.

Animals↗
PubMed2005

High-frequency phase variation of Vibrio vulnificus 1003: isolation and characterization of a rugose phenotypic variant.

The marine bacterium Vibrio vulnificus is a human pathogen that can spontaneously switch between virulent opaque and avirulent translucent phenotypes. Here, we document an additional form, the rugose variant, which produces copious biofilms and which may contribute both to pathogenicity of V. vulnificus and to its survival under adverse environmental conditions.

Biofilms↗
PubMed2003

MECP2 mutations or polymorphisms in mentally retarded boys: diagnostic implications.

BACKGROUND: Among the well characterized X-linked conditions causing mental retardation, mutations in the methyl-CpG-binding protein 2 gene (MECP2) in Xq28 have been found in up to 85% of patients with Rett syndrome, a neurologic disorder which, in addition to other symptoms, severely affects higher cognitive functions in females. Mutations in the MECP2 gene are involved in a broad spectrum of phenotypes from classical Rett syndrome to mild intellectual difficulties in females and neonatal encephalopathy in males. Recently, mutations in the MECP2 gene were reported in males with non-specific mental retardation suggesting that defects in MECP2 could be responsible for up to 2% of X-linked mental retardation. METHODS: We screened by denaturing high-pressure liquid chromatography the entire coding region and flanking intronic sequences of the MECP2 gene in a cohort of 354 mentally retarded males found negative for an expansion across the FRAXA CGG repeat and in a family in which a boy and his sister were mentally retarded. RESULTS: We identified mainly silent polymorphisms within the MECP2 gene, together with four sequence alterations of unknown significance, i.e. three missense mutations (T197M, T228S, and P376S) and one substitution at position -19 in intron 3 (378-19delT). Further familial investigations allowed us to ruled out a pathogenic effect for the intronic variant, the T228S and the P376S missense mutations. CONCLUSIONS: These results confirm that MECP2 mutations in males are far more rare than initially thought and call for a careful evaluation of the pathogenicity of the MECP2 missense mutations identified in mentally retarded males before genetic counseling is proposed to the relatives.

Chromatography, High Pressure Liquid↗
PubMed2026

INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report.

Congenital muscular dystrophies (CMDs) are a genetically heterogeneous group of disorders. Variants in the INPP5K gene, which encodes a phosphoinositide phosphatase, are a rare cause of CMD. The condition is commonly associated with muscle weakness, early-onset cataracts, and intellectual disability, and prior reports have primarily identified missense, frameshift, or deletion variants. We describe the first Chinese case of INPP5K-related muscular dystrophy in a 28-year-old male with a mild phenotype, notably lacking intellectual disability. His presentation included bilateral cataracts at age 5 and adolescent onset limb girdle weakness. Muscle magnetic resonance imaging (MRI) revealed a characteristic pattern of selective fatty infiltration, with severe involvement of gluteal and thigh muscles and striking sparing of the rectus femoris, sartorius, and gracilis. Genetic analysis identified compound heterozygous novel INPP5K variants: a missense c.274C>T, p.(Arg92Cys) and a synonymous c.261G>A, p.(Lys87=) change. Functional studies confirmed the synonymous variant causes aberrant splicing (exon 3 skipping), leading to a frameshift and premature termination p.(Leu52SerfsTer49). According to American College of Medical Genetics and Genomics guidelines, the c.274C>T and c.261G>A variants were classified as likely pathogenic and pathogenic, respectively. This first report of a Chinese patient with INPP5K-related muscular dystrophy broadens both the genetic and clinical spectrum of the disorder. We identify the first disease-causing synonymous variant (via aberrant splicing) and a novel hypomorphic missense variant p.(Arg92Cys), the combination of which explains the attenuated phenotype lacking intellectual disability. Our case highlights the critical role of RNA analysis in diagnosing non-canonical variants and confirms the universal diagnostic relevance of the characteristic muscle MRI pattern.

Adult↗
PubMed2026

Analysis of Genetic Factors in a Family With Short Stature.

BACKGROUND: To elucidate the genetic underpinnings of short stature in a familial cohort of five individuals. METHODS: A family with a history of short stature from Zhongnan Hospital of Wuhan University was the subject of this study. Peripheral blood samples were collected from family members for whole exome sequencing and Sanger sequencing to identify genetic anomalies. RESULTS: The male proband, aged 3&#x2009;years and 10&#x2009;months, had significant growth retardation, with a height of 91&#x2009;cm (<&#x2009;3rd percentile) and a weight of 13&#x2009;kg (<&#x2009;3rd percentile). Whole exome sequencing identified a missense mutation in the COL1A2 gene (c.577G>A, p.Gly193Ser) with maternal inheritance. Sanger sequencing confirmed this mutation in the mother and half-sister. According to American College of Medical Genetics and Genomics (ACMG) guidelines, this variant was classified as likely pathogenic. Additionally, a heterozygous mutation in the GH1 gene (c.291+1G>A) was detected in the father and grandfather, contributing to the familial short stature phenotype. CONCLUSION: In this family, we identified that variants in the COL1A2 and the GH1 can each cause short stature. This reflects both the genetic consistency and complexity of short stature, which is highly dependent on comprehensive genetic testing.

Humans↗
PubMedDate not supplied

[Dissociative phases and pathogenicity of different species of the Bacillus genus].

The previously postulated hypothesis, according to which different species of the genus Bacillus show strictly similar morphological and biological properties when the same variants are considered, has been confirmed by the present research. The "S" (smooth) variants of the five studied species (B. anthracis, B. subtilis, B. cereus, B. megaterium, B. mesentericus) are all lethal, at the experimented dose, for mice, whereas the "R" (rough, "star-shaped" colonies) variant of the same strains of the same species are all not pathogenic for the same animals. Likewise the "S" variants of three species tested in guinea pigs showed to be pathogenic; particularly B. anthracis and B. subtilis were lethal, whereas B. cereus caused a black eschar like that one described in the cutaneous anthrax. The "RS" variant ("medusae head" surface colonies) is not pathogenic for mice and guinea pigs (even B. anthracis) if the tested strains are cultivated for years in ordinary solid nutrient media; the same morphological variants are strongly pathogenic (also B. subtilis), when the strains are recently isolated from infected animals. The similarity between the same "S" variants of different species is proved also by the protection given by anti-anthrax serum to animals infected by B. subtilis.

Animals↗
PubMed2006

Analysis of LMP1 variants of EBV in Southern Thailand: evidence for strain-associated T-cell tropism and pathogenicity.

BACKGROUND: The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) has sequence heterogeneity. Some of the variants are associated with altered tumorigenic activity and show geographically specific localization. In Thailand, the EBV genome is frequently detected in circulating T cells of T-cell diseases. OBJECTIVE: To determine the role of EBV LMP1 variation in the genesis of T-cell diseases, we focused on virus factors and analyzed EBV strains in Thailand. STUDY DESIGN: EBV DNA was extracted from 18 healthy individuals and 45 patients with T-cell diseases in Southern Thailand and 30 healthy individuals in Central Thailand. By using PCR-direct sequencing method, nucleotide sequences corresponding to the carboxyl terminus of the LMP1 were determined. RESULTS: Four known strains, B95-8 prototype, China 1, China 2 and Mediterranean (Med) and two novel strains, Southeast Asia 1 (SEA 1) and Southeast Asia 2 (SEA 2) were identified. The prevalence of China 2 strain was significantly different (p=0.006) between Central and Southern Thailand. Higher prevalence (p=0.026) of 30-bp deletion type in the Southern Thais was observed. The LMP1 Med strain was associated with the worse prognosis (p=0.029). Among T-cell diseases patients, CD3(+)-cell oriented infection was recognized in SEA1 strain (p=0.025). CONCLUSION: The distribution of EBV strains may be associated with geographic/ethnic and clinical background in the Thai population. Certain EBV strains defined by their LMP1 sequence may influence cell tropism, disease association, or disease severity.

Amino Acid Sequence↗
PubMed2004

Identification of allelic variants of the bovine immune regulatory molecule CEACAM1 implies a pathogen-driven evolution.

Carcinoembryonic antigen-related cell adhesion molecule (CEACAM1), the primordial member of the carcinoembryonic antigen (CEA) family, functions as a MHC-independent natural killer (NK) cell inhibitory receptor, regulates T and B cell proliferation, and induces dendritic cell (DC) maturation. Despite these fundamental functions, CEACAM1 and most of the CEA family members differ significantly in primates and rodents. A number of diverse murine and human pathogens use CEACAM1 as a cellular receptor, indicating that the observed species-specific differences are the result of divergent molecular pathogen/host coevolution. To gain deeper insight into its evolution and function, we cloned CEACAM1 cDNA from cattle as a representative of a third mammalian order. Bovine CEACAM1 differs considerably from rodent and primate CEACAM1 due to deletion of the B domain exon which was most likely caused by insertion of LINE/SINE sequences and reveals alternative splicing within the transmembrane exon. However, the characteristic long and short isoforms exist which contain or lack the typical immunoreceptor tyrosine-based inhibitory motifs (ITIM) in their cytoplasmic tails, respectively. Bovine peripheral blood lymphocytes (PBL) express only ITIM-containing CEACAM1 isoforms, and upregulate their expression upon stimulation, suggesting an inhibitory function in these cells. As found in rodents, two clearly distinct CEACAM1 alleles exist in cattle. In the a allele, a unique deletion of three amino acids is found in the N domain, which is important for pathogen binding in mice and humans. This is consistent with the notion that CEACAM1 serves or has served as a pathogen receptor in cattle.

Alleles↗
PubMed1996

Local antibody production in the oviduct and gut of hens infected with a variant strain of infectious bronchitis virus.

Following infection of 16-week old specific pathogen-free (SPF) female chickens with an enterotropic variant of infectious bronchitis virus (IBV) strain G, IBV-specific Immunoglobulin G (IgG) and IgA were detected in tears, tracheal washes, oviduct washes, duodenal and caecal contents using class-specific monoclonal antibodies in enzyme linked immunosorbent assays (ELISA). IgG antibody content was highest in tears on Day 7 post-infection (p.i.) and was still detectable on Day 23 p.i. Significant levels of IgG antibody were present in oviduct washes on Days 7 and 23 p.i. Tears showed the highest IgA antibody concentration of any sample on Day 7 p.i. but this decreased to an insignificant level by Day 17 p.i. Oviduct and tracheal washes had IgA antibodies on Day 7 p.i. Significant levels of both antibody classes were detected in duodenal contents on Day 17 p.i. only but neither was present in caecal contents. Using a method which compares titre of antibody produced from pieces of tissue at 4 degrees C with that at 37 degrees C as an indicator of local secretion, IgG and IgA antibody synthesis was demonstrated in the Harderian gland on Days 7 and 17 p.i. Local IgG antibody synthesis was seen in the oviduct on Day 7 p.i. but on Day 23 p.i. the optical density at 4 degrees C was higher than at 37 degrees C, suggestive of high concentrations of extracellular antibody. In a separate experiment, passively administered IBV antibody transuded from serum into oviduct washes but did not do so in the trachea. In a third experiment, ELISA and haemagglutination-inhibition (HI) titres of serum and oviduct washes from ten hens previously infected when day-old were compared with egg production. Maximum positive correlation was seen between HI titres of oviduct washes and egg production.

Animals↗