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At least 919 records · Page 51Linked to original sources
PubMed2005

Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration.

BACKGROUND: The haplotype H1 of the tau gene, MAPT, is highly associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). OBJECTIVE: To investigate the pathogenic basis of this association. METHODS: Detailed linkage disequilibrium and common haplotype structure of MAPT were examined in 27 CEPH trios using validated HapMap genotype data for 24 single nucleotide polymorphisms (SNPs) spanning MAPT. RESULTS: Multiple variants of the H1 haplotype were resolved, reflecting a far greater diversity of MAPT than can be explained by the H1 and H2 clades alone. Based on this, six haplotype tagging SNPs (htSNPs) that capture 95% of the common haplotype diversity were used to genotype well characterised PSP and CBD case-control cohorts. In addition to strong association with PSP and CBD of individual SNPs, two common haplotypes derived from these htSNPs were identified that are highly associated with PSP: the sole H2 derived haplotype was underrepresented and one of the common H1 derived haplotypes was highly associated, with a similar trend observed in CBD. There were powerful and highly significant associations with PSP and CBD of haplotypes formed by three H1 specific SNPs. This made it possible to define a candidate region of at least approximately 56 kb, spanning sequences from upstream of MAPT exon 1 to intron 9. On the H1 haplotype background, these could harbour the pathogenic variants. CONCLUSIONS: The findings support the pathological evidence that underlying variations in MAPT could contribute to disease pathogenesis by subtle effects on gene expression and/or splicing. They also form the basis for the investigation of the possible genetic role of MAPT in Parkinson's disease and other tauopathies, including Alzheimer's disease.

Aged↗
PubMed2000

Clinical consequences of molecular diagnosis in families with mismatch repair gene germline mutations.

Hereditary nonpolyposis colorectal cancer (HNPCC), clinically defined by the Amsterdam criteria, is associated with mismatch repair gene germline mutations. This study was performed to evaluate the efficiency of combined clinical and molecular diagnostics in identifying carriers of a mutated gene in families meeting criteria of the Bethesda guidelines and to examine the influence of molecular diagnosis on clinical decision-making in carriers and noncarriers. Seventy-two patients meeting criteria of the Bethesda guidelines were tested for microsatellite instabilities (MSI). MSI-H tumors were found in 38 (52.8%) index patients. Complete sequencing of hMLH1 and hMSH2 in 38 MSI-H patients and of hMSH6 in one of these patients revealed 15 pathogenic germline mutations, including three novel mutations, and three novel unclassified germline variants. Twelve of the 15 pathogenic mutations were found in patients fulfilling the Amsterdam I/II criteria. Surgical and genetic counseling was offered to the affected families; as a result of molecular diagnosis in the 15 families, 26 index patients and affected carriers and 8 asymptomatic carriers of a mutated mismatch repair gene were included in the surveillance program, and 26 noncarriers were excluded from this program. Although germline mutations are detected in only 20.8% of patients fulfilling criteria of the Bethesda guidelines, family history and MSI-H tumor classification are both strong indicators for germline mutations in hMSH2, hMLH1, and hMSH6 genes, resulting in a 51.9% mutation detection rate. Identification of individual mutation status allows clear-cut decisions on whether or not inclusion in surveillance programs is indicated.

Adaptor Proteins, Signal Transducing↗
PubMed2025

Evolutionary adaptations of a pediatric pathogen: low-inflammatory and high-resistance phenotypes in the emerging Salmonella typhimurium monophasic variant 1,4,[5],12:i:

Salmonella enterica serovar 1,4,[5],12:i:- (S.1,4,[5],12:i:-), a monophasic variant of Salmonella typhimurium (S. typhimurium), is an emerging multidrug-resistant pathogen posing a significant threat to pediatric health. Research on this variant remains limited, and due to challenges associated with traditional identification methods, S.1,4,[5],12:i:- has often been misclassified as S. typhimurium. This study collected clinical data from 122 children infected with S.1,4,[5],12:i:- and 42 with traditional S. typhimurium in Fujian Province, China, between 2014 and 2023. Whole-genome sequencing was used for strain analysis. Our findings revealed that 77.87% of children with S.1,4,[5],12:i:- infection were aged between 1 month and 2 years. Compared with traditional S. typhimurium, children with S.1,4,[5],12:i:- exhibited milder clinical symptoms, as evidenced by lower levels of the inflammatory marker C-reactive protein (16.53 mg/L vs. 33.94 mg/L, P < 0.05) and a lower hospitalization rate (26.23% vs. 42.86%, P < 0.05). These differences may be attributed to the high carriage rate of the anti-inflammatory gene gogB in S.1,4,[5],12:i:- (95.08% vs. 16.67%, P < 0.0001). Additionally, S.1,4,[5],12:i:- exhibited a higher resistance rate to multiple antibiotics, particularly ceftriaxone, than traditional S. typhimurium (32.79% vs. 7.14%, P < 0.001). This increased resistance may be associated with the carriage of the IncHI2/IncHI2A plasmid. The S.1,4,[5],12:i:- ST34 clone prevalent in this region aligns with the global epidemic trend but exhibits greater genetic diversity. Overall, the stealthy evolutionary adaptation of low-inflammation and high-resistance provides novel insights into this variant's global dominance. These findings underscore the importance of heightened clinical awareness and targeted interventions, particularly for vulnerable pediatric populations. IMPORTANCE S.1,4,[5],12:i:- poses a growing global health threat, particularly endangering infants and young children. Characterized by increasing prevalence, multidrug resistance, and diagnostic challenges, this variant demonstrates milder inflammatory responses yet stronger antibiotic resistance than traditional S. typhimurium in pediatric infections. Crucially, we identified its unique "low-inflammation, high-resistance" evolutionary strategy associated with anti-inflammatory gene gogB and resistance plasmid IncHI2/IncHI2A. The stealthy evolutionary adaptation provides novel insights into this variant's global dominance, while offering critical guidance for improving clinical management and formulating targeted public health measures to protect vulnerable pediatric populations against this cunning pathogen.

Humans↗
PubMed2006

R104H may suppress transthyretin amyloidogenesis by thermodynamic stabilization, but not by the kinetic mechanism characterizing T119 interallelic trans-suppression.

The tetrameric protein transthyretin (TTR) forms amyloid fibrils upon dissociation and subsequent monomer misfolding, enabling misassembly. Remarkably, the aggregation of one of over 100 destabilized TTR variants leads to familial amyloid disease. It is known that trans-suppression mediated by the incorporation of T119M subunits into tetramers otherwise composed of the most common familial variant V30M, ameliorates disease by substantially slowing the rate of tetramer dissociation, a mechanism referred to as kinetic stabilization of the native state. R104H TTR has been reported to be non-pathogenic, and recently, this variant has been invoked as a trans-suppressor of amyloid fibril formation. Here, we demonstrate that the trans-suppression mechanism of R104H does not involve kinetic stabilization of the tetrameric structure, instead its modest trans-suppression most likely results from the thermodynamic stabilization of the tetrameric TTR structure. Thermodynamic stabilization increases the fraction of tetramer at the expense of the misfolding competent monomer decreasing the ability of TTR to aggregate into amyloid fibrils. As a consequence of this stabilization mechanism, R104H may be capable of protecting patients with modestly destabilizing mutations against amyloidosis by slightly lowering the overall population of monomeric protein that can misfold and form amyloid.

Amino Acid Substitution↗
PubMed1996

Pathogenesis of plaque variants of porcine reproductive and respiratory syndrome virus in pregnant sows.

OBJECTIVE: To determine whether porcine reproductive and respiratory syndrome virus plaque variants vary in their pathogenicity in causing late-term reproductive failure. DESIGN: Four groups of 2 sows each at 86 days of gestation were inoculated intranasally with PRRSV small (MN-Hs) and large (MN-HI) plaque variants, field isolate, and cell culture medium, respectively. In addition, 2 sows each at 86 days of gestation were inoculated intranasally or IM with MN-Hs virus. ANIMALS: 14 pregnant sows. PROCEDURE: Inoculated sows were allowed to deliver at term, and each litter was examined for clinical abnormality and presence of virus. RESULTS: Two sows infected with MN-Hs virus delivered 14 live and 5 dead pigs, whereas 2 sows infected with MN-HI virus delivered 0 live and 25 dead pigs. Two sows inoculated with a field isolate (MN-W) delivered 10 live and 20 dead pigs. Two control sows had 26 normal fetuses at slaughter at 107 days of gestation. Virus was isolated from 16 (66.7%) of 24 liveborn pigs, 9 (64.3%) of 14 stillborn pigs, and 3 (12.0%) of 25 mummified fetuses of the 6 infected sows. Subsequently, 4 MN-Hs-infected sows delivered 40 live and 11 dead pigs. CONCLUSIONS: Marked difference in the pathogenicity in pregnant sows between porcine reproductive and respiratory syndrome virus strains was documented. The MN-Hs virus is considered to be of low pathogenicity, but the other viruses are highly pathogenic for late-term pregnant sows.

Animals↗
PubMed2004

Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas.

Clear-cut inherited Mendelian traits, such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer, account for <4% of colorectal cancers. Another 20% of all colorectal cancers are thought to occur in individuals with a significant inherited multifactorial susceptibility to colorectal cancer that is not obviously familial. Incompletely penetrant, comparatively rare missense variants in the adenomatous polyposis coli gene, which is responsible for familial adenomatous polyposis, have been described in patients with multiple colorectal adenomas. These variants represent a category of variation that has been suggested, quite generally, to account for a substantial fraction of such multifactorial inherited susceptibility. The aim of this study was to explore this rare variant hypothesis for multifactorial inheritance by using multiple colorectal adenomas as the model. Patients with multiple adenomas were screened for germ-line variants in a panel of candidate genes. Germ-line DNA was obtained from 124 patients with between 3 and 100 histologically proven synchronous or metachronous adenomatous polyps. All patients were tested for the adenomatous polyposis coli variants I1307K and E1317Q, and variants were also sought in AXIN1 (axin), CTNNB1 (beta-catenin), and the mismatch repair genes hMLH1 and hMSH2. The control group consisted of 483 random controls. Thirty of 124 (24.9%) patients carried potentially pathogenic germ-line variants as compared with 55 ( approximately 12%) of the controls. This overall difference is highly significant, suggesting that many rare variants collectively contribute to the inherited susceptibility to colorectal adenomas.

Adenoma↗
PubMed1996

A comparative study of unpassaged and animal passaged cultures of Listeria monocytogenes in rabbits.

Variants of a parent culture of Listeria monocytogenes were prepared by passaging it several times through rabbits. The resulting isolates (V1 to V6) were investigated and compared with the parent culture with particular emphasis on their phenotypic characters and their pathogenicity for rabbits. The variants maintained the morphological, cultural, biochemical and serological features of the parent strain. Although no significant decrease was noted in the total extracellular protein produced, 10 mg/ml of a 6-day culture broth grown at 34 degrees C for V6 as compared to 12.3 mg/ml for the parent culture, the phosphocholine-specific phospholipase C (PC-PLC) activity diminished with passaging. Pathogenicity for rabbits, as determined by viable count of the organism per gram of the infected organ, increased at each passage. Animals infected with V6 revealed a mean of 2.2 x 10(9) CFU/g of spleen as compared to the parent culture which had a count of 5.0 x 10(6) CFU/g. These observations indicate a lack of direct correlation between in vitro production of PC-PLC and virulence of L. monocytogenes for rabbits.

Animals↗
PubMed2007

R1514Q substitution in Lrrk2 is not a pathogenic Parkinson's disease mutation.

Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing.

Adenine Nucleotide Translocator 1↗
PubMed2005

Role of domestic ducks in the propagation and biological evolution of highly pathogenic H5N1 influenza viruses in Asia.

Wild waterfowl, including ducks, are natural hosts of influenza A viruses. These viruses rarely caused disease in ducks until 2002, when some H5N1 strains became highly pathogenic. Here we show that these H5N1 viruses are reverting to nonpathogenicity in ducks. Ducks experimentally infected with viruses isolated between 2003 and 2004 shed virus for an extended time (up to 17 days), during which variant viruses with low pathogenicity were selected. These results suggest that the duck has become the "Trojan horse" of Asian H5N1 influenza viruses. The ducks that are unaffected by infection with these viruses continue to circulate these viruses, presenting a pandemic threat.

Animals↗
PubMed1988

Development of Host Range Mutants of Xanthomonas campestris pv. translucens.

Xanthomonas campestris pv. translucens is the causal agent of bacterial leaf streak of cereal grains and grasses, and individual strains within the pathovar differ in their host range among the cereals. Coinoculation of a wide-host-range and a narrow-host-range strain resulted in the wide-host-range reaction. Transposon and chemical mutagenesis of the wide-host-range strain Xct4, pathogenic on barley, wheat, rye, and triticale, resulted in variants with reduced host range. When pathogenicity was inactivated independently for barley, wheat, triticale, and rye, wild-type symptoms were retained on the other members in the host range. Testing of some host range mutants on additional varieties of the cereals indicated some cultivar specificity. In addition, mutants nonpathogenic on combinations of the hosts or on all hosts were isolated. This suggests that there are independent positive factors determining host range in this species, rather than an avirulence gene system such as those determining race specificity in other plant pathogens.

Journal Article↗
PubMed1993

Multiple viral determinants contribute to pathogenicity of the acutely lethal simian immunodeficiency virus SIVsmmPBj variant.

Simian immunodeficiency virus (SIV) induces an immunodeficiency syndrome similar to human AIDS. Although the disease course of SIV-induced immunodeficiency is generally measured in months to years, a disease syndrome that results in death in 5 to 14 days has been described in pig-tailed macaques infected with the SIVsmmPBj (PBj) strain. The purpose of this study was to derive an acutely lethal PBj molecular clone in order to study viral genes involved in pathogenesis. Six infectious molecular clones were generated; acutely fatal disease was induced by experimental inoculation of pig-tailed macaques with virus stocks derived from either of two clones, PBj6.6 or PBj14.6. Molecular chimeras were constructed by exchange of regions of the genome of PBj6.6 and a nonlethal, related clone, SIVsmH4. Only a chimera expressing the PBj genome under the control of a SIVsmH4 long terminal repeat induced death soon after inoculation. These studies suggest that multiple viral genes of PBj are critical for development of acute disease. More specifically, the env gene but not the long terminal repeat PBj was required for acute disease induction; however env must act in concert with another gene(s) of the PBj genome.

Animals↗
PubMed1992

Pathogenicity of feline leukemia virus is commonly associated with variant viruses.

Many of the serious diseases resulting from feline leukemia virus (FeLV) infection are associated with the generation of novel variant viruses. The prototype FeLV-A virus is highly stable and circulates in the cat population without apparent antigenic change. However, recombination with cellular oncogenes produces viruses which cause leukemia or other malignant diseases. Other recombinants within the env genes of FeLV-A and endogenous FeLV are recognized as belonging to a second subgroup, FeLV-B, the presence of which is correlated with an increased risk of infection with FeLV and a higher incidence of leukemia. Mutants of FeLV which affect the env gene are phenotypically of a third subgroup, FeLV-C, and have a close association with erythroid aplasia. None of these viruses, apart from FeLV-B, is transmitted further in nature. Therefore the generation of these novel viruses and the production of disease is an inadvertent consequence of FeLV infection.

Anemia↗
PubMed1989

Molecular and biological properties of a variant of avian influenza A/Seal/Massachusetts/1/80 (H7N7) virus that is pathogenic for mice.

A/Seal/Mass/80 influenza virus has been shown to be closely related antigenically and genetically to avian influenza H7N7 viruses, however, the virus does not replicate efficiently in avian species but does replicate in most mammals, except mice (Hinshaw et al., Infect. Immun., 34, 351-361, 1981). In order to develop a model defining the molecular changes that occur during acquisition of virulence, the A/Seal/Mass/80 virus was adapted to growth in mouse lungs. The adaptation was accompanied by changes in a number of properties of the haemagglutinin as well as by changes in other genes of the virus as determined by RNA: RNA hybridization.

Animals↗
PubMed2002

Gastric gross and microscopic lesions caused by the UNAM-97 variant strain of infectious bronchitis virus after the eighth passage in specific pathogen-free chicken embryos.

Herein we report a description of gross and microscopic lesions found in specific pathogen-free chicken embryos caused by UNAM-97 infectious bronchitis virus (IBV) variant strain after the eighth passage. Embryos were divided into three groups and were inoculated in the chorioallantoic sac with 0.2 mL of UNAM-97, Mass 41 IBV (positive control), or sterile PBS (negative control). Forty-eight hours later the allatoic fluid was taken and used to start a cycle of eight passages through 9-d-old embryos. Seven days after the last passage, embryos were harvested and macroscopic lesions in all organs were recorded. Proventriculus and gizzard samples were obtained from all embryos and routinely processed for microscopic and ultrastructural examinations. The UNAM-97 IBV variant strain caused two macroscopic lesions uncommon for Mexican strains: thin-walled proventriculus and gizzard, as well as urate accumulation within an extra-embryonic peritoneal sac, leaving the body through the umbilical duct and accompanied by the yolk sac. At microscopic level, two relevant findings were observed to be produced by this variant. In the proventriculus, there was a decrease in the gland papillary branching, while the gizzard showed a significant reduction in mucosa thickness and tubular-to-proliferative-cell ratio, as well as an absence of hyaline secretion in the lumen. Electrodense material scattered in proventricular and gizzard cells was observed, with a structure consistent with that of coronaviruses. These pathological chicken embryo findings have not been reported as being caused by other IBV strains in Mexico.

Animals↗
PubMed2026

A novel deep intronic EIF2AK3 variant disrupts splicing and causes Wolcott-Rallison syndrome.

AIM: Deep intronic variants can disrupt splicing and cause monogenic disease but are missed by routine genetic testing. This study assessed the contribution of deep intronic variants to Wolcott-Rallison syndrome (WRS), a recessive disorder characterized by early-onset diabetes and progressive multisystem disease caused by loss-of-function EIF2AK3 variants. METHODS: We investigated a cohort of 116 individuals referred to the Exeter Genomics Laboratory for genetic testing who had diabetes diagnosed at &#x2264;2&#x2009;years and at least one additional feature consistent with WRS: hepatic dysfunction, skeletal abnormalities or developmental delay. No genetic cause had been identified after testing all known early-onset diabetes genes. We screened genome-sequencing data for rare homozygous intronic EIF2AK3 variants. Candidate variants predicted to affect splicing by SpliceAI were assessed using a minigene exon-trapping assay. RESULTS: We identified two rare homozygous intronic EIF2AK3 variants in two siblings. Only one variant, c.1651-180G>T, was predicted to disrupt splicing in silico. The two children, born to consanguineous parents, were diagnosed with early-onset diabetes (diagnosed at 1&#x2009;year and 21&#x2009;weeks), hepatic dysfunction, skeletal abnormalities, developmental delay, thyroid dysfunction, hip dysplasia and gait abnormalities. The minigene assay showed that c.1651-180G>T creates a cryptic donor splice site within intron 9, resulting in inclusion of a 79-nucleotide pseudoexon, causing a frameshift and premature stop codon. Using this evidence, the variant was reclassified as likely pathogenic according to ACMG/ACGS guidelines. CONCLUSIONS: We report the first deep intronic EIF2AK3 variant causing WRS, highlighting the need to consider systematic intronic analysis in unresolved cases.

EIF2AK3↗
PubMed2004

BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer.

In order to evaluate the role of BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer, 97 patients with sporadic breast cancer were analyzed for mutations in the BRCA1 and BRCA2 coding regions, by using a combination of fluorescent-conformation sensitive gel electrophoresis (F-CSGE) and direct sequencing. Fifty-five distinct sequence variants were detected, which included three pathogenic truncating mutations, 15 missense mutations, 16 polymorphisms, and 21 intronic variants. Twenty-six of these variants have never been previously reported and may be of Korean-specific origin. Two pathogenic BRCA1 mutations (c.922_924delinsT, c.5445G>A) and one pathogenic BRCA2 mutation (c.2259delT) were observed, and two of these (BRCA1 c.5445G>A and BRCA2 c.2259delT) are novel. The total prevalence of germline pathogenic mutations in BRCA1 and/or BRCA2 in Korean sporadic breast cancer is estimated to be about 3.1%. Considering that the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of germline BRCA mutations in sporadic breast cancer patients. Further study using a larger sample size is required to determine the merits of genetic diagnosis and counseling in breast cancer patients.

Adult↗
PubMed2007

Pathogenicity of the Lrrk2 R1514Q substitution in Parkinson's disease.

An increasing number of nonsynonymous LRRK2 variants are being reported as putative pathogenic mutations. We identified one large kindred harboring the Lrrk2 R1514Q substitution; however, the variant did not segregate fully with disease. Combined analyses of three case-control series demonstrate that the R1514Q substitution is not associated with increased risk of disease (OR: 1.3; 95% CI: 0.6-2.8; P = 0.45). These findings highlight the importance of using family-based studies and multiple population screenings when examining the association of these polymorphic LRRK2 gene variants with Parkinson's disease.

Aged↗