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At least 1,189 records · Page 66Linked to original sources
PubMed2026

Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease.

Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3, encoding a ubiquitous endosomal 2Cl-/H+ exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3-related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9.

Chloride Channels↗
PubMedDate not supplied

Evaluation of a commercial quail pox vaccine (Bio-Pox Q) for the control of "variant" fowl poxvirus infections.

Groups of 3-week-old specific pathogen-free chickens immunized with a commercial live-virus quail pox vaccine (Bio-Pox Q) were not protected against challenge with "variant" poxviruses isolated from chickens that were previously vaccinated with commercial fowl pox vaccine. The percentages of vaccinated chickens resistant to challenge with each of the five variant field isolates were 0%, 20%, 0%, 20%, and 10%, respectively. However, when immunity engendered by the variant field isolates was challenged with the commercial quail pox vaccine virus, 80%, 70%, 80%, 50%, and 60% of the vaccinates, respectively, were protected. Results from cross-immunity studies indicate that the commercial quail pox vaccine does share some immunologic relationship with these variant poxvirus field isolates, but not enough to be used in the control of some outbreaks of pox caused by variant poxviruses.

Animals↗
PubMed2006

Assessing the pathogenicity of MLH1 missense mutations in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with clinical, genetic and functional features.

Assessing the pathogenicity of missense mutations of MLH1 and MSH2 is critical to counsel patients with suspected hereditary nonpolyposis colorectal cancer (HNPCC). Approximately 32% of all MLH1 mutations and 18% of MSH2 mutations are missense variants which often have an uncertain genetic significance. To assess the pathogenicity of four MLH1 missense mutations which were found in five patients with suspected HNPCC, P648S (CCC --> TCC), L559R (CTG --> CGG), K618A (AAG --> GCG), Y646C (TAT --> TGT), we studied their ability to disrupt MLH1 protein function and their relationship with all those clinical, genetic and pathological features which are typical of this syndrome. Our results indicated that the P648S and L559R mutations were probably pathogenic because they disrupted MLH1 protein interaction with its partner PMS2 in vitro and abolished MLH1 expression in HCT116 cells. In addition these variants were associated with features often found in HNPCC patients: in particular high microsatellite instability, occurrence of high grade tumours and, in one case, strong family history. The pathogenicity of the K618A and Y646C mutations was questionable as their correlation with features typical of HNPCC was low and the outcome of the functional analysis was ambiguous. These observations suggested that a clinically usable assessment of the pathogenicity of MLH missense variants can be achieved through the analysis of multiple mutation characteristics among which loss of protein function, occurrence of microsatellite instability and family history seemed to have a predominant role.

Adaptor Proteins, Signal Transducing↗
PubMed1968

Experience in the study of a live vaccine made from the TP-21 strain of Malayan Langat virus.

The reaction-causing properties and immunogenicity of 2 cloned variants of the Malayan tick virus, Langat TP-21 strain, were studied. One clone, which was not pathogenic for rhesus monkeys when inoculated intracerebrally, caused the formation of antibody in moderate titre against tick-borne encephalitis virus in over 70% of persons given 2 inoculations of a live vaccine prepared from it. The other variant, which was pathogenic for rhesus monkeys, was characterized by greater immunogenicity but when given as a live vaccine caused acutely febrile reactions and other side-effects in 10% of inoculated persons 6 to 8 days after administration.In persons vaccinated with the avirulent vaccine, the antibodies were maintained for over 3 years compared with only 1 year after administration of a killed vaccine. The live vaccine made from the non-pathogenic clone of the Langat virus proved to be suitable for revaccinating patients inoculated with the killed vaccine. The vaccine prepared from the non-pathogenic clone could be more extensively employed for the prophylaxis of tick-borne encephalitis.

Encephalitis, Tick-Borne↗
PubMed1987

Pathogenic and structural properties of wild type infectious bursal disease virus (IBDV) and virus grown in vitro.

Large plaque (LP) and small plaque (SP) variants of Infectious Bursal Disease Virus (IBDV) which are formed in vitro after serial passages in CE-cells at low or high multiplicities of infection were tested for their pathogenic properties in susceptible chickens. LP virus caused clinical manifestations and destruction of the Bursa of Fabricius (BF) without killing the animals. No signs of a disease appeared after infection with SP virus, and only limited necrotic foci developed in the BF. Coinfection with the SP variant and the highly pathogenic wild type (wt) virus reduced mortality and the severity of the disease. In contrast to the SP variant, which forms incomplete particles of low density, with one or the other of the two genomic RNA segments missing, the two RNA segments characteristic for IBDV were present in approximately equal amounts in wt particles with a buoyant density of 1.29 g/ml isolated from the BF. In spite of an almost total replacement of one of the two major structural polypeptides with a molecular weight of 32 kd by a 28 kd protein, infectivity in this low density fraction was only slightly reduced. This finding underlines the importance of the type of post-translational modification in lymphoid cells or fibroblasts.

Animals↗
PubMed1994

Monoclonal IgA class-switch variants against bacterial surface antigens: molecular forms and transport into murine respiratory secretions.

The present study describes a new model for passive immunization of the respiratory tract with IgA in comparison to other isotypes. Monoclonal IgA-isotype-switch variants were isolated from different IgG-producing hybridoma clones specific for surface epitopes of bacterial respiratory tract pathogens. Analysis of the molecular form of the IgA variants revealed the simultaneous production of monomeric, dimeric and higher polymeric IgA by a single-cell line with predominance of the polymeric forms. The specificities of the IgA variants were identical to the parent IgG antibodies as demonstrated by inhibition experiments. The IgA variant antibodies were separated into monomers and polymers by gel filtration. Intravenous injection of the different molecular forms of IgA and of IgG into mice were used to investigate the transport characteristics of IgA into murine upper and lower respiratory tract secretions by the physiological route in comparison to IgG. Polymeric IgA variant, monomeric IgA variant and IgG were detected in immunologically active form in both nasal secretion and bronchoalveolar fluid as evidenced by binding to their antigens in an enzyme-linked immunosorbent assay. The relative contribution of the specific exogenous monoclonal IgA and monoclonal IgG to total IgA and IgG, respectively, was determined in secretions. Comparison of the secretion to serum transport ratios clearly indicates selective transport of polymeric IgA variant into nasal secretions relative to IgG parent antibody. Molecular and functional characteristics of the IgA variants make them ideal for passive mucosal immunization experiments and identification of protective epitopes in mucosal immunity.

Animals↗
PubMed2001

Detection of mutations in the COL4A5 gene by SSCP in X-linked Alport syndrome.

Alport syndrome is a progressive renal disease leading to chronic renal failure, which often is accompanied by sensorineural deafness and ophthalmological signs in the form of anterior lenticonus. The X-linked form of the disease is caused by mutations in the COL4A5 gene encoding the alpha5-chain of type IV-collagen. We performed mutation analysis of the COL4A5 gene by PCR-SSCP analysis of each of the 51 exons with flanking intronic sequences in 81 patients suspected of X-linked Alport syndrome including 29 clear X-linked cases, 37 cases from families with a pedigree compatible with X-linked inheritance, and 15 isolated cases. We found a mutation detection rate of 52% (42/81) (58% in males and 21% in females), and 69% (20/29) in families who clearly demonstrated X-linked inheritance. Thirty-six different mutations were found in 42 patients comprising 16 missense mutations, seven frameshifts, three in-frame deletions, four nonsense mutations, and six splice site mutations. Twenty-two of the mutations have not previously been reported. Furthermore, we found one non-pathogenic amino acid substitution, one rare variant in a non-coding region, and one polymorphism with a heterozygosity of 28%. Three de novo mutations were found, two of which were paternal and one of maternal origin.

Codon, Nonsense↗
PubMed2004

Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans, affecting 1 in 3500 individuals. NF1 is a fully penetrant exhibiting a mutation rate some 10-fold higher compared to most other disease genes. As a consequence, a high number of cases (up to 50%) are sporadic. Mutation detection is complex due to the large size of NF1 gene, the presence of pseudogenes and the great variety of lesions. In the present study we attempted to delineate the NF1 mutational spectrum in the Italian population reporting four-year experience with the direct analysis of the whole NF1 coding region in 110 unrelated subjects affected by NF1. For each patient, the whole coding sequence and all splice sites were studied for mutations, either by the protein truncation test (PTT), or, most often, by denaturing high performance liquid chromatography (DHPLC). Mutations were identified in 75 (68%) patients. Twenty-two mutations were found to be novel. The detection rate for the different methods was 7/18 (39%) for PTT, and 68/103 (66%) for DHPLC. The mutations were evenly distributed along the NF1 coding sequence. Thirty-two of the 75 unrelated NF1 patients in which germline mutations were identified (32/75, 43%) harbour 23 different recurrent mutations. Fifteen sequence variants likely to represent non-pathogenic polymorphisms were observed at the NF1 locus. Genotype-phenotype analysis was unable to detect any obvious correlation.

Chromatography, High Pressure Liquid↗
PubMed1993

The pathogenesis of wild type and drug resistant mutant strains of bovine herpesvirus-1 (BHV-1) in the natural host.

An experimental infection with bovine herpesvirus-1 was established in calves by means of intranasal inoculation. Three calves were infected with the parental strain BHV-1 w/t, three with the TK-defective strain, B 1 and four with the HPMPA-resistant strain, 3 A. Inoculation with w/t virus resulted in a reproducible clinical disease characterised by respiratory distress, fever and the presence of virus in nasal mucus. Following the acute infection, w/t-inoculated animals became seropositive for BHV-1 specific antibody. The TK-defective mutant (BHV-1 B 1) produced an acute infection similar to the parental virus in all three calves inoculated. The HPMPA-resistant mutant (BHV-1 3 A), however, showed a reduced pattern of infection and virus of lower titre was isolated from three of four calves; the antibody responses were generally lower, and one calf remained seronegative until reactivation. Following stimulation with dexamethasone 72 days after the primary inoculation, virus was re-isolated from all wild type-inoculated calves. In contrast, no evidence of reactivation was obtained from the three B 1-inoculated animals. However, all four animals inoculated with the mutant 3 A showed virus reactivation including the calf which had remained seronegative following primary virus inoculation. Previous studies have suggested that drug-resistance mutations in herpesviruses frequently are associated with reduced pathogenicity on the basis of experiments in laboratory models. The importance of the present study is the demonstration that two different drug-resistant variants of an alpha herpesvirus both have altered pathogenicity in the natural host for that infection. These results also have implications for the design and use of attenuated vaccine strains.

Adenine↗
PubMed2005

Diversity of virulence patterns among shiga toxin-producing Escherichia coli from human clinical cases-need for more detailed diagnostics.

Intestinal infections due to shiga toxin-producing Escherichia coli bacteria (STEC) reveal a broad range of clinical symptoms and a large scale of virulence properties of the respective pathogens. The question whether all STEC variants or only a particular group of them need to be considered for clinical and epidemiological purposes was answered throughout this study. Using the PCR technique for the identification of 25 different virulence-associated genes, 266 E. coli strains belonging to 81 different E. coli serotypes from various clinical origins were investigated. A great genetic diversity of the virulence properties and a broad range of virulence marker combinations have been identified. However, distinct virulence marker combinations (e.g. Stx2/LEE/pO157 as well as Stx2dac/pO113) were found to be associated with the same notified clinical symptoms (e.g. HUS). Such an association speaks either for the "shiga toxin-only concept" or for several redundant, but clinically or epidemiologically important virulence properties.

DNA, Bacterial↗
PubMed2004

Molecular analysis of the cytoadherence phenotype of a Plasmodium falciparum field isolate that binds intercellular adhesion molecule-1.

The ability of Plasmodium falciparum-infected erythrocytes to adhere to endothelial receptors and sequester in diverse host organs is an important pathogenic mechanism. Cytoadherence is mediated by variant surface antigens, which are referred to as PfEMP-1 and are encoded by var genes. The extracellular regions of PfEMP-1 contain multiple conserved cysteine-rich domains that are referred to as Duffy-binding-like (DBL) domains. Here, we analyze the adhesive phenotype of an Indian P. falciparum field isolate, JDP8, which binds ICAM-1 but does not bind CD36. This is a unique cytoadherence phenotype because P. falciparum strains that bind ICAM-1 described thus far usually also bind CD36. Moreover, binding to both receptors is thought to be important for static adhesion under flow. The ICAM-1 binding population of P. falciparum JDP8 adheres to endothelial cells under flow despite poor binding to CD36. We have also identified an expressed var gene, JDP8Icvar, which mediates the ICAM-1 binding phenotype of JDP8. Expression of different regions of JDP8Icvar on the surface of COS-7 cells followed by binding assays demonstrates that the ICAM-1 binding domain maps to the DBL2betaC2 domain of JDP8Icvar. Sequence comparison with two previously identified ICAM-1 binding domains of PfEMP-1, which also map to DBLbetaC2 domains, suggests that diverse P. falciparum isolates use a structurally conserved domain to bind ICAM-1. It thus appears that functional constraints may place limits on the extent of sequence diversity in receptor-binding domains of PfEMP-1.

Amino Acid Sequence↗
PubMed2005

Genetic variation in Taenia solium.

Neurocysticercosis is a major zoonotic larval cestode infection that has a worldwide distribution and is of significant public health importance. Knowledge of the genetic structure of Taenia solium can be applied to the epidemiology and transmission of this disease, since genetic variants may differ in infectivity and pathogenicity. Molecular epidemiological approaches can also enable detailed studies of transmission. On a global scale, mitochondrial markers have differentiated between T. solium isolates from Asia and isolates from Africa/Latin America. Intraspecific variation in T. solium has been detected to some extent, using RAPD markers to differentiate between T. solium populations from different regions within Mexico. Markers currently available for T. solium have not been used to analyse genetic variation at the community or local level. The development of highly polymorphic markers such as microsatellites in T. solium can provide the means to examine genetic heterogeneity of tapeworm infection at the household, community and regional level. Preliminary studies suggest it is possible to analyse population genetic variation in communities using a range of polymorphic markers.

Animals↗
PubMed2003

Evaluation of PARVG located on 22q13 as a candidate tumor suppressor gene for colorectal and breast cancer.

Colorectal cancer (CRC) and breast cancer constitute common neoplasms in Western countries and leading causes of cancer-related death. Development and progression of both malignancies occur as a multistep process, requiring the activation of oncogenes and the inactivation of several tumor suppressor genes. Our group has recently identified a minimal region of deletion on 22q13 involved in CRC and breast cancer patients, which is highly indicative of the existence of a tumor suppressor gene (or genes). We performed mutation analysis of the PARVG gene, one of the genes present on the 22q13 region of interest, which has been previously demonstrated to have a reduced expression in some cancer cell lines. We have identified several DNA variants that are not compatible with pathogenic mutations. Accordingly, PARVG appears not to be a tumor suppressor gene involved in CRC and breast cancer development and progression.

Base Sequence↗
PubMed1998

Developmental selection of var gene expression in Plasmodium falciparum.

The protozoan Plasmodium falciparum causes lethal malaria. Adhesion of erythrocytes infected with P. falciparum to vascular endothelium and to uninfected red blood cells (rosetting) may be involved in the pathogenesis of severe malaria. The binding is mediated by the antigenically variant erythrocyte-membrane-protein-1 (PfEMP-1), which is encoded by members of the P. falciparum var gene family. The control of expression and switching of var genes seems to lack resemblance to mechanisms operating in variant gene families of other microbial pathogens. Here we show that multiple, distinct var gene transcripts (about 24 or more) can be detected by reverse transcription and polymerase chain reaction in bulk cultures of the rosetting parasite FCR3S1.2, despite the adhesive homogeneity of the cultures. We also detected several var transcripts in single erythrocytes infected with a ring-stage parasite of FCR3S1.2, and found that different var genes are transcribed simultaneously from several chromosomes in the same cell. In contrast, we detected only one var transcript, FCR3S1.2 var-1, which encodes the rosetting PfEMP-1 protein, in individual rosette-adhesive trophozoite-infected cells, and we found only one PfEMP-1 type at the erythrocyte surface by labelling with 125iodine and immunoprecipitation. We conclude that a single P. falciparum parasite simultaneously transcribes multiple var genes but, through a developmentally regulated process, selects only one PfEMP-1 to reach the surface of the host cell.

Adult↗
PubMed2000

The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity.

Originally identified as a cell surface receptor that triggered the death of lymphocytes and tumor cells, it is now recognized that Fas (also known as CD95 or Apo-I) has distinct functions in the life and death of different cell types in the immune system. Fas signaling may also be involved in T cell costimulation and proliferation. Although Fas deficiency in humans and mice predisposes them towards systemic autoimmunity, Fas-FasL interactions can also facilitate organ-specific immunopathology. Proximal signaling by Fas and related receptors depends on subunit preassembly, which accounts for the dominant-negative effect of pathogenic receptor mutants and natural splice variants.

Animals↗
PubMed2003

Adverse events in the prophylaxis of haemophilia.

Whilst prophylaxis undoubtedly offers many advantages, the potential for adverse effects must also be borne in mind. Modern plasma-derived products have an extremely good safety record with regard to transmission of pathogens, although continuous vigilance is required as new pathogens continue to emerge, eg new variant Creutzfeldt-Jakob disease. There is no evidence that prophylactic treatment is associated with an increased incidence of inhibitors, and it is now recognized that genetic factors are the most significant in conferring susceptibility. Although subtle immunological abnormalities have also been observed in patients with haemophilia, there is no evidence that these are of any clinical significance. There has been a growing trend to use indwelling venous catheters for prophylaxis. The risk of infection has been appreciated for some time, although it has only recently been possible to quantify this with more precision. The risk of catheter-associated thrombosis is now recognized to be higher than hitherto appreciated. Whilst sporting activities are to be encouraged, there is a potential for significant trauma in children with prophylaxis, as plasma coagulation factor levels remain far below normal with the usual regimens.

Blood Coagulation Factors↗
PubMed2000

Mitochondrial DNA segregation in the developing embryo.

Mitochondrial (mt)DNA is strictly maternally inherited in mammals; new mutations thus segregate along maternal lineages without the benefit of homologous recombination with mtDNA of paternal origin. Despite the high mtDNA copy number (approximately 100000 or more) in mature oocytes, and despite the relatively small number of cell divisions during oogenesis, mtDNA sequence variants segregate rapidly between generations. This paradoxical behaviour has been ascribed to the presence of a mtDNA 'bottleneck' in oogenesis or early embryogenesis. The nature and size of this bottleneck have been the subject of much controversy. This review argues that segregation of mtDNA sequence variants in the female germline occurs primarily during mitosis in the oocyte precursor population. Segregation is rapid because the precursor cells (primordial germ cells and oogonia) contain a relatively small number of mtDNA templates (the bottleneck) and because the replication of mtDNA is under relaxed control. For the most part, the process appears similar in mice segregating polymorphic sequence variants and in human pedigrees segregating pathogenic point mutations. In particular, there is no evidence for selection against high levels of pathogenic mtDNA point mutations in oogenesis, in early embryonic development, or in fetal development, thus suggesting that efficient respiratory chain function is not critical until post-natal life. These results have important practical implications for clinical genetics.

Chromosome Segregation↗