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At least 1,153 records · Page 64Linked to original sources
PubMed2004

Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese finnish children and adults.

Two Finnish cohorts, comprising 56 children with severe early-onset obesity (relative weight for height greater than or equal to +70% before age 10) and 252 morbidly obese adults (body mass index, > or = 40 kg/m(2)), were screened for melanocortin-4 receptor (MC4R) mutations. We identified a pathogenic mutation (S127L) in one child, causing severe early-onset obesity. We describe the phenotype of this particular mutation for the first time. We also identified a novel (I226T) polymorphism in the coding and two new variations (-439delGC and 1059C>T) outside the coding region of the MC4R gene. Three previously described polymorphisms (V103I, T112M, and I125L) were identified. In vitro functional studies of variants T112M, S127L, and I226T supported a pathogenic role of the S127L mutation, because signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired. The S127L mutation did not affect receptor inhibition by the antagonist agouti-related protein. Localization of the three variant receptors was similar to that of wild type. In conclusion, a pathogenic MC4R mutation was found among subjects with severe early-onset obesity but not among morbidly obese adults. Impaired function of the S127L receptor was due to reduced activation, not a defect of protein transport to the cell membrane.

Adolescent↗
PubMed2026

PubMind: literature-based genetic variant extraction and functional annotation using large language models.

Biomedical literature contains extensive functional knowledge on genetic variants, but much remains inaccessible in unstructured text. Existing resources such as ClinVar and HGMD remain limited by coverage, submission bias, update frequency, and sparse annotation. We develop PubMind, an artificial intelligence (AI) framework that uses large language models (LLMs) to triage and extract variant-function-disease associations and supporting evidence from biomedical text. PubMind captures single-nucleotide, copy-number, structural, and gene-fusion variants, and normalizes records to genomic and transcriptomic coordinates. Benchmarking shows >90% accuracy for variant recognition and 99% precision for disease extraction. Applied to >41 million PubMed abstracts and >5 million full-text articles, PubMind generates PubMind-DB, a database of ~1.3 million unique variants with contextual annotations, accessible via web interface and API. Only ~10% of PubMind variants overlap with ClinVar, and >80% of them show concordant pathogenicity labels. PubMind transforms unstructured biomedical text into structured genomic knowledge, advancing variant interpretation for precision medicine.

Large Language Models↗
PubMed1975

Small- and large-plaque variants of Chikungunya virus in two vertebrate and seven invertebrate cell lines.

Nine cells lines--BHK-21, Vero, Aedes albopictus, A. aegypti (monolayer and howwow vesicles), A. w-albus, A. vittatus, Anopheles stephensi and Culex quinquefasciatus--were infected with small- and large-plaque (SP, LP) variants of chikungunya virus. Ross strain, and incubated at different temperatures. In the Aedes (29 plus or minus 1 degrees C) and the vertebrate cell lines (36 degrees C), infectivity titers of extracellular virus rapidly reached a peak; cytopathic effect (CPE) occurred only in the latter. In Anopheles cells (29 plus or minus 1 degrees C), infectivity titers increased very slowly to a peak at 10 days post-inoculation (p.i.); in Culex cells (29 plus or minus 1 degrees C or room temperature), persistence of virus only or no multiplication was observed. In infected A. albopictus, A. aegypti and A. w-albus carrier cultures, the SP variant continued to resemble the original stock virus in terms of mouse pathogenicity and plaque morphology in Vero cells, but the LP variant tended to modify toward the SP variant.

Aedes↗
PubMed2005

Small transthyretin (TTR) ligands as possible therapeutic agents in TTR amyloidoses.

In transthyretin (TTR) amyloidosis TTR variants deposit as amyloid fibrils giving origin, in most cases, to peripheral polyneuropathy, cardiomyopathy, carpal tunnel syndrome and/or amyloid deposition in the eye. More than eighty TTR variants are known, most of them being pathogenic. The mechanism of TTR fibril formation is still not completely elucidated. However it is widely accepted that the amino acid substitutions in the TTR variants contribute to a destabilizing effect on the TTR tetramer molecule, which in particular conditions dissociate into non native monomeric intermediates that aggregate and polymerize in amyloid fibrils that further elongate. Since this is a multi-step process there is the possibility to impair TTR amyloid fibril formation at different stages of the process namely by tetramer stabilization, inhibition of fibril formation or fibril disruption. Till now the only efficient therapy available is liver transplant when performed in an early phase of the onset of the disease symptoms. Since this is a very invasive therapy alternatives are desirable. In that sense, several compounds have been proposed to impair amyloid formation or disruption. Based on the proposed mechanism for TTR amyloid fibril formation we discuss the action of some of the proposed TTR stabilizers such as derivatives of some NSAIDs (diflunisal, diclofenac, flufenamic acid, and derivatives) and the action of amyloid disrupters such as 4'-iodo-4'-deoxydoxorubicin (I-DOX) and tetracyclines. Among all these compounds, TTR stabilizers seem to be the most interesting since they would impair very early the process of amyloid formation and could also have a prophylactic effect.

Amyloid↗
PubMed2004

Developing inhibitors to selectively target two-component and phosphorelay signal transduction systems of pathogenic microorganisms.

Two-component signal transduction systems and their expanded variants known as phosphorelays are integral elements of the virulence and antimicrobial resistance responses of a wide range of pathogenic bacteria and fungi and also regulate essential functions. As a consequence, two-component systems and phosphorelays are recognized targets for the development of novel antimicrobial agents and a number of chemically synthesized inhibitors from different chemical classes have been identified by compound library screens. However, in the majority of cases these compounds do not appear to be selective for signal transduction pathways and exert their effect by multiple mechanisms of action. The key to designing molecules to selectively disrupt signal transduction may lie with the conserved features of response regulators and the structural analysis of complexes of signaling proteins.

Anti-Infective Agents↗
PubMed2005

Sequence variation in mitochondrial complex I genes: mutation or polymorphism?

BACKGROUND: Defects of the mitochondrial genome are recognised as common causes of genetic disease. Sequencing of large portions or even the entire mitochondrial genome is routine in many laboratories for the investigation of mitochondrial disease. However, establishing whether a detected sequence change is polymorphic or pathogenic is still a major difficulty because of its highly polymorphic nature. This has major implications for the patient and the family. OBJECTIVE: To describe a scoring system for determining the likelihood that a given sequence variant in one of the seven mitochondrially encoded complex I (MTND) genes is truly pathogenic. RESULTS: The scoring system was applied to 50 reported MTND mutations. Using this system, 21 of the mutations analysed fell into the group of neutral sequence variants, 10 were classified as possibly pathogenic, three as probably pathogenic, and 16 as almost certainly pathogenic. CONCLUSIONS: The proposed scoring system should advance the interpretation of sequence variants and ensure that candidate pathogenic mutations are rigorously investigated.

DNA, Mitochondrial↗
PubMed1987

Phase variation in Bordetella pertussis is accompanied by changes in DNA modification.

Pathogenic strains of Bordetella pertussis tend to undergo a phase variation process when propagated in vitro. The phase variants do not express part or all of the virulence factors of the pathogenic strain and are phenotypically stable. We have previously shown that variation involves a non-reversible, non-random process. In an attempt to characterize the molecular changes accompanying phase variation, chromosomal DNA, isolated from B. pertussis and its variants, was digested with a variety of restriction enzymes followed by agarose gel electrophoresis. While variant DNA was digested by all tested enzymes, pathogenic strain DNA was not digested by part of the enzymes, thus suggesting modification of the DNA at specific sites. DNA isolated from reversible, growth medium induced variants, demonstrated sensitivity to digestion identical to that of spontaneous, stable variants. Analysis of the restriction sequences of all the enzymes, which did not digest DNA from pathogenic strains, failed to reveal any common sequence known to be affected by methylation. HPLC and nearest-neighbor analysis showed a 2-fold increase in the level of DNA methylation in the pathogenic strain. It was concluded that (a) the chromosomal DNA in virulent strains of B. pertussis is protected against enzymatic digestion by an as yet unknown modification and (b) variation in B. pertussis may be caused by changes in the modification of the DNA rather than by mutation.

Base Sequence↗
PubMed2005

Identification of HPV variants.

The vast majority of anogenital carcinomas are caused by high-risk human papillomaviruses (HPVs), and among Western nations HPV-16 is usually the most predominant cancer-associated type. As a DNA virus, HPV type 16 has a relatively stable genome that is believed to have co-evolved with its host over the millennia. Nevertheless, among the "wild" populations of HPV-16 that are circulating, a large number of variants have been identified, and these may have considerably different pathogenic potentials. In this chapter, methods for screening and characterizing HPV-16 sequence variants are described. In particular, we describe methods for the identification of variation within the HPV-16 E5 open reading frame and for the detection of the nt 131 A-->G mutation of the E6 ORF, using restriction fragment length polymorphism assays. In addition, we describe approaches for DNA sequencing and analysis. Such methods are likely to be of particular interest to those involved in epidemiological investigations of virus transmission and pathogenicity studies.

Base Sequence↗
PubMed2006

Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation.

The cause of mental retardation in one-third to one-half of all affected individuals is unknown. Microscopically detectable chromosomal abnormalities are the most frequently recognized cause, but gain or loss of chromosomal segments that are too small to be seen by conventional cytogenetic analysis has been found to be another important cause. Array-based methods offer a practical means of performing a high-resolution survey of the entire genome for submicroscopic copy-number variants. We studied 100 children with idiopathic mental retardation and normal results of standard chromosomal analysis, by use of whole-genome sampling analysis with Affymetrix GeneChip Human Mapping 100K arrays. We found de novo deletions as small as 178 kb in eight cases, de novo duplications as small as 1.1 Mb in two cases, and unsuspected mosaic trisomy 9 in another case. This technology can detect at least twice as many potentially pathogenic de novo copy-number variants as conventional cytogenetic analysis can in people with mental retardation.

Child↗
PubMed1994

Sequence analysis of two porcine rotaviruses differing in growth in vitro and in pathogenicity: distinct VP4 sequences and conservation of NS53, VP6 and VP7 genes.

The VP4, VP7, NS53 and VP6 genes of two porcine rotavirus variants which differ in their in vitro growth properties and pathogenicity have been cloned and sequenced. The VP4 genes show only 67.2% nucleic acid and 70.6% amino acid identity. The VP4 gene of one variant (4S) is closely related to that of the bovine UK rotavirus strain, whereas the VP4 gene of the other variant (4F) is only distantly related to known VP4 genes and is likely to represent a new P serotype. In contrast the NS53 (VP5), VP6 and VP7 genes of the 4F and 4S variants show greater than 99% nucleotide and amino acid identity, indicating that the two viruses are genetically related by a reassortment event. The implications for the role of VP4 in the determination of in vitro growth characteristics and pathogenicity are discussed.

Amino Acid Sequence↗
PubMed2004

Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing.

L1 disease is a clinically heterogeneous X-chromosomal neurodevelopmental disorder that is frequently associated with mental retardation and congenital hydrocephalus in males. It is caused by mutations in L1CAM that encodes a multifunctional transmembrane neuronal cell adhesion molecule. We report our findings on 6 novel intronic L1CAM sequence variants (c.523+5G>A, c.1123+1G>A, c.1547-13delC, c.3323-17dupG, c.3457+3A>T, and c.3457+18C>T), and a recurrent one (c.523+12C>T). While the pathogenic potential of nucleotide changes within the evolutionarily well-conserved splice consensus sequence (c.523+5G>A, c.1123+1G>A, and c.3457+3A>T) is widely accepted, it is not always straight forward to assess the disease relevance of intronic mutations, if they lie outside the consensus. The c.523+12C>T variant co-segregated with X-linked hydrocephalus in two unrelated families. In the mutated allele, a preferentially used novel splice donor site is generated that results in a frame shift due to insertion of the first 10 bp of intron 5 in the mature mRNA, a largely truncated protein, and most likely a functional null allele. The c.1547-13delC mutation creates a new acceptor site resulting in the insertion of 4 additional amino acids at the end of the immunoglobulin like domain 5. In contrast, c.3323-17dupG and c.3457+18C>T seem to be non-pathogenic L1CAM variants.

Base Sequence↗
PubMed1994

Nuclear ribosomal DNA variation and pathogenic specialization in alternaria fungi known to produce host-specific toxins.

A total of 99 strains of 11 Alternaria species, including 68 strains of seven fungi known to produce host-specific toxins, were subjected to analysis of restriction fragment length polymorphism (RFLP) in nuclear ribosomal DNA (rDNA). Total DNA was digested with XbaI, and the Southern blots were probed with a nuclear rDNA clone of Alternaria kikuchiana. The hybridization gave 17 different RFLPs from the 99 strains. On the basis of these RFLPs, populations of host-specific toxin-producing fungi could not be differentiated from one another nor from nonpathogenic A. alternata. Each population of the toxin-producing fungi carried rDNA variants. Nine different types, named A1 to A6 and B1 to B3, were detected among the toxin-producing fungi and nonpathogenic A. alternata. All of the populations contained the type A4 variant, and the other rDNA types were also shared by different toxin-producing fungi and A. alternata. In contrast, Alternaria species that are morphologically distinguishable from A. alternata could be differentiated from A. alternata on the basis of the rDNA RFLPs. Polymorphisms in rDNA digested with HaeIII and MspI were also evaluated in 61 Alternaria strains. These restriction enzymes produced 31 variations among all of the samples. The seven toxin-producing fungi and nonpathogenic A. alternata could not be resolved by phylogenetic analysis based on the RFLPs, although they could be differentiated from the other Alternaria species studied. These results provide support for the hypothesis that Alternaria fungi known to produce host-specific toxins are intraspecific variants of A. alternata specialized in pathogenicity.

Journal Article↗
PubMed2006

Pathological and physiological functions of presenilins.

Mutations in PSEN1 and PSEN2 genes account for the majority of cases of early-onset familial Alzheimer disease. Since the first prediction of a genetic link between PSEN1 and PSEN2 with Alzheimer's disease, many research groups from both academia and pharmaceutical industry have sought to unravel how pathogenic mutations in PSEN cause presenile dementia. PSEN genes encode polytopic membrane proteins termed presenilins (PS1 and PS2), which function as the catalytic subunit of gamma-secretase, an intramembrane protease that has a wide spectrum of type I membrane protein substrates. Sequential cleavage of amyloid precursor protein by BACE and gamma-secretase releases highly fibrillogenic beta-amyloid peptides, which accumulate in the brains of aged individuals and patients with Alzheimer's disease. Familial Alzheimer's disease-associated presenilin variants are thought to exert their pathogenic function by selectively elevating the levels of highly amyloidogenic Abeta42 peptides. In addition to Alzheimer's disease, several recent studies have linked PSEN1 to familiar frontotemporal dementia. Here, we review the biology of PS1, its role in gamma-secretase activity, and discuss recent developments in the cell biology of PS1 with respect to Alzheimer's disease pathogenesis.

Journal Article↗
PubMed1988

[Sphingolipidosis. Recent progress in biochemical diagnosis. New pathogenic approaches].

In an increasing number of biochemical variants of the sphingolipidoses, demonstration of the enzyme defect cannot be achieved by the (briefly summarized) conventional techniques. Alternative methods allowing diagnosis of such patients - in particular metabolic studies in living cell cultures - are discussed. The current knowledge and practical impact of molecular biology in the sphingolipidoses field is shortly reviewed. The authors finally discuss the recent findings highlighting in Niemann-Pick disease type C metabolic abnormalities in the cellular processing of cholesterol and their consequences on diagnosis and pathogenesis of this disorder.

Cells, Cultured↗
PubMed1985

Lesions induced in the respiratory tract of chickens by encapsulated or nonencapsulated variants of Haemophilus paragallinarum.

Lesions induced in chickens by an encapsulated or nonencapsulated strain of Haemophilus paragallinarum were investigated. In terms of lesion severity, major differences in pathogenicity were observed between the encapsulated and nonencapsulated variants. The principal lesion manifested by the encapsulated variant was an acute catarrhal inflammation of the upper respiratory tract, mainly of the nasal cavity and paranasal sinus. Infiltration of a large number of mast cells into the lamina propria of the mucous membrane of the nasal cavity was also characteristic. Numerous organisms were found on the cilia or on the surface of the epithelial cells of the nasal mucosa. Chickens with these histologic lesions had severe clinical signs of coryza, and organisms were recovered in high numbers from the nasal cavity and paranasal sinus. In contrast, chickens that were given the nonencapsulated variant did not have clinical signs of coryza, and the organisms were recovered in low numbers from the inoculated sites; slight histopathologic lesions were observed in the nasal mucosa at postinoculation day 1. Mast cell infiltration in the chickens inoculated with the encapsulated variant indicated that mast cells may be responsible for producing clinical signs of coryza via the activation of pharmacologic mediators. Adherence to and colonization of the encapsulated variant on the nasal mucosa seems to be a first step of the infection.

Animals↗
PubMed1981

Genome structure of mouse hepatitis virus: comparative analysis by oligonucleotide mapping.

Several natural variants of mouse hepatitis viruses have been compared by the T1-oligonucleotide fingerprinting technique. In general, they have diverged quite extensively. However, MHV-3, a hepatotropic strain, and A59, a nonpathogenic strain, were found to be extremely related. Yet, each of them contains 2-4 specific oligonucleotides. One of the MHV-3-specific oligonucleotides was mapped in 30S poly(A)-containing RNA or 6-7 Kb from the 3-end and the other near the 5'-end of the genome. These two genetic regions might be associated with viral pathogenicity. In addition, two JHM plaque variants, DL producing large plaques and DS producing small plaques, were also compared. They share almost all T1-oligonucleotides, but each contains one unique spot. The DL-specific oligonucleotide was mapped in 21S poly(A)-containing RNA or at about 4 kb from the 3'-end. Finally, the MHV genome was found to contain the "cap" structure, confirming that it is a positive-stranded RNA.

Animals↗
PubMed2001

Secreted variant of nucleoside diphosphate kinase from the intracellular parasitic nematode Trichinella spiralis.

The molecular components involved in the survival of the parasitic nematode Trichinella spiralis in an intracellular environment are poorly characterized. Here we demonstrate that infective larvae secrete a nucleoside diphosphate kinase when maintained in vitro. The secreted enzyme forms a phosphohistidine intermediate and shows broad specificity in that it readily accepts gamma-phosphate from both ATP and GTP and donates it to all nucleoside and deoxynucleoside diphosphate acceptors tested. The enzyme was partially purified from culture medium by ATP affinity chromatography and identified as a 17-kDa protein by autophosphorylation and reactivity with an antibody to a plant-derived homologue. Secreted nucleoside diphosphate kinases have previously been identified only in prokaryotic organisms, all of them bacterial pathogens. The identification of a secreted variant of this enzyme from a multicellular eukaryote is very unusual and is suggestive of a role in modulating host cell function.

Animals↗