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PubMed2001

Association of genetic mutations in Plasmodium vivax dhfr with resistance to sulfadoxine-pyrimethamine: geographical and clinical correlates.

Mutations in the Plasmodium falciparum gene (dhfr) encoding dihydrofolate reductase are associated with resistance to antifols. Plasmodium vivax, the more prevalent malaria parasite in Asia and the Americas, is considered antifol resistant. Functional polymorphisms in the dhfr gene of P. vivax (pvdhfr) were assessed by PCR-restriction fragment length polymorphism using blood samples taken from 125 patients with acute vivax malaria from three widely separated locations, Thailand (n = 100), India (n = 16), and Madagascar and the Comoros Islands (n = 9). Upon evaluation of the three important codons (encoding residues 57, 58, and 117) of P. vivax dhfr (pvdhfr), double- or triple-mutation genotypes were found in all but one case from Thailand (99%), in only three cases from India (19%) and in no cases from Madagascar or the Comoros Islands (P < 0.0001). The dhfr PCR products of P. vivax from 32 Thai patients treated with the antifolate sulfadoxine-pyrimethamine (S-P) were investigated. All samples showed either double (53%) or triple (47%) mutations. Following treatment, 34% of the patients had early treatment failures and only 10 (31%) of the patients cleared their parasitemias for 28 days. There were no significant differences in cure rates, but parasite reduction ratios at 48 h were significantly lower for patients whose samples showed triple mutations than for those whose samples showed double mutations (P = 0.01). The three mutations at the pvdhfr codons for residues 57, 58, and 117 are associated with high levels of S-P resistance in P. vivax. These mutations presumably arose from selection pressure.

Adult↗
PubMed2026

Genetic mutations driving ciprofloxacin resistance in laboratory-evolved Salmonella Typhimurium.

Ciprofloxacin resistance in Salmonella Typhimurium is a significant public health concern, and the mechanisms by which the resistance evolves are poorly defined. Here, by serial passaging under antibiotic selection, we isolated ciprofloxacin-resistant S. Typhimurium mutants and subjected them to whole-genome sequencing to reveal the major mutations associated with resistance. The Low CipR mutant acquired four chromosomal mutations in ramR, icdA, lipB, and gyrA, and the High CipR mutant gained additional mutations in gyrB, yaiC, and corA. Functional characterization determined that mutations in ramR resulted in efflux pump upregulation, while disruptions in the TCA cycle caused by mutations in icdA and lipB led to metabolic alterations. These changes indirectly enhanced resistance by increasing the expression of the global regulator MarA and reducing OmpF-dependent membrane permeability. Despite the observation of the G105A substitution in GyrA, enzymatic assays confirmed the failure to support resistance to ciprofloxacin, possibly because the structural alteration remained minimal. GyrB488-489dup was associated with maintained supercoiling under ciprofloxacin and enhanced fluoroquinolone resistance, suggesting a major role in resistance evolution. Other mutations in yaiC impaired biofilm and, in corA, intracellular accumulation of magnesium, possibly stabilizing the bacterial cell envelope under antibiotic pressure. The findings provide novel explanations for the multifaceted mechanisms leading to ciprofloxacin resistance in Salmonella and suggest targets to combat antimicrobial resistance.IMPORTANCEAntibiotic resistance in Salmonella Typhimurium is an increasing public health concern, yet the genetic changes that allow bacteria to become resistant are not fully understood. In this study, we evolved ciprofloxacin-resistant Salmonella in the laboratory and identified the mutations that arise during resistance development. We found that resistance does not result from a single change but from multiple adaptations affecting drug efflux, metabolism, and the antibiotic target. Some mutations increased the activity of pumps that remove antibiotics from the cell, while others altered bacterial metabolism and reduced membrane permeability, making it harder for the drug to enter. A duplication in the DNA gyrase subunit GyrB played a particularly important role in maintaining DNA function under antibiotic stress. Together, these results reveal how diverse genetic changes cooperate to generate ciprofloxacin resistance and provide insights that may help guide strategies to combat drug-resistant Salmonella infections.

DNA gyrase↗
PubMed2000

The influence of age, sex, vitamin B(12), folate levels and methylenetetrahydrofolate reductase C677T genetic mutations on plasma homocysteine in the Chinese population.

BACKGROUND AND OBJECTIVES: Thromboembolic diseases remain a major cause of morbidity and mortality in most countries. The present study was thus conducted to determine the influences of age, sex, the methylenetetrahydrofolate reductase (MTHFR) gene mutation and the B vitamins on the plasma homocysteine (Hcy) levels in the Chinese. Our previous study found that Chinese carry the same mutation of the methylenetetrahydrofolate reductase (MTHFR) gene described in Western populations, with a 677CAET substitution being another possible cause of thrombosis. DESIGN AND METHODS: The study population comprised 445 consecutively enrolled Chinese subjects of different ages and sex. Overall 69 subjects were found to have homozygous 677CAET mutation of the MTHFR gene, and were classified as Group I; 164 subjects were found to have heterozygous mutation and classified as Group II; 212 had no such mutation and were classified as Group III. RESULTS: The mean plasma Hcy did not differ significantly between these 3 groups. When each group was divided again by gender, we found that both age and plasma Hcy levels were significantly higher in the males than in the females. In addition to Hcy levels, we also measured plasma vitamin B(12) and folate levels in 258 randomized subjects. Univariate and multivariate analysis showed MTHFR mutation could affect Hcy level, and univariate and multivariate analysis showed that age, MTHFR mutation and vitamin B(12) could affect the log(Hcy) levels. INTERPRETATION AND CONCLUSIONS: We demonstrate that some Chinese carry the 677CAET mutation of the methylenetetrahydrofolate reductase gene. This could affect their homocysteine levels and thus be a risk factor for thromboembolic disease.

Age Factors↗
PubMed2026

Genetic mutations within tva receptor gene confer resistance to ALV-A and ALV-K infection in chickens.

Avian leukosis virus subgroup A (ALV-A) and the newly emerging subgroup K (ALV-K) are primary causative pathogens of avian leukosis in chickens and continue to pose a persistent threat to poultry industry worldwide. Susceptibility or resistance of chicken cells to ALV-A and ALV-K is determined by the tva receptor gene. Indeed, six ALV-A resistant alleles (tvar1-tvar6) have been identified within the tva gene. However, whether these tva alleles confer resistance to ALV-K infection remains unclear. In this study, we identified five tva resistant alleles, namely tvar2, tvar3, tvar4, tvar5, and tvar6, in Qingyuan partridge chickens (QYPC). In vitro analyses, including flow cytometry and quantitative real-time PCR, we demonstrated that the tvar2 allele confers complete resistance to both ALV-A and ALV-K infection. In contrast, the tvar3, tvar4, tvar5, and tvar6 alleles each significantly reduced susceptibility to ALV-K. Furthermore, these in vitro observations were corroborated by in vivo infection experiments, which confirmed that the tvar2 allele consistently conferred complete resistance to both ALV-A and ALV-K, while tvar3, tvar4, tvar5, and tvar6 alleles each resulted in a significant reduction in ALV-K susceptibility. Additionally, the tvar2-tvar6 alleles were broadly distributed across QYPC lines, with notably high frequencies of resistant genotypes observed in specific QYPC populations. Collectively, these findings not only expand our understanding of tva-mediated resistance to both ALV-A and ALV-K but also provide valuable genetic targets for selective breeding programs aimed at enhancing resistance to ALV-A and ALV-K in chickens.

ALV-A↗
PubMed1990

Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency.

Human lactate dehydrogenase-A mutant gene was isolated from the genomic DNA library of a patient deficient in LDH-A (Muscle) subunit. The nucleotide sequences of seven protein-coding exons were determined and a deletion of 20 base-pairs in exon 6 was found. This mutation results in a frame-shift translation and premature termination. The predicted incomplete LDH-A (M) subunit containing only 259 instead of 331 amino acids appears to be degraded rapidly, since no protein was detected immunologically (Maekawa et al., Am J Hum Genet 39:232-238, 1986). In addition, three synonymous (silent) substitutions, A to C, T to C, and G to A, were observed at codons 115, 160 and 172, respectively, in this LDH-A mutant gene.

Amino Acid Sequence↗
PubMed2003

Congenital secondary hypothyroidism due to a mutation C105Vfs114X thyrotropin-beta mutation: genetic study of five unrelated families from Switzerland and Argentina.

We identified five patients with congenital secondary hypothyroidism with isolated thyrotropin (TSH) deficiency originating from three and two unrelated Argentinean and Swiss families, respectively. The affected patients presented with both low TSH as well as low thyroid hormone levels. Further, TSH-releasing hormone (TRH) stimulation failed to increase serum TSH, whereas prolactin increased adequately. These affected children were homozygous for a 1-bp deletion (822delT) in the TSH-beta subunit gene leading to a cysteine 105 to valine conversion (C105V) and to a frameshift with a premature stop codon at position 114 (C105Vfs114X). In a total of 22 families five different mutations located within the coding region of the TSH-beta subunit gene responsible for congenital secondary hypothyroidism have been reported so far (E12X; G29R; Q49X; IVS2 +5, G --> A; C105Vfs114X). Importantly, out of 13 families, including our five families, the C105Vfs114X mutation has been described in 12 unrelated and non-consanguineous families, whereas the remaining four TSH-beta subunit gene mutations have been described in consanguineous families only. Therefore the C105Vfs114X mutation within the TSH-beta subunit gene is the most frequent alteration causing congenital secondary hypothyroidism (13 of 22; 59%) and occurs mainly in unrelated and non-consanguineous families (12 of 13; 92%). As we could exclude a common ancestry by microsatellite marker analysis in our five independent families we concluded that the codon 105 in the TSH-beta subunit gene might be a "hot spot," although a founder effect has been reported in certain cases clustered in a highly specific and restricted geographical area.

Adolescent↗
PubMed2004

Common bacterial toxins and physiological vulnerability to sudden infant death: the role of deleterious genetic mutations.

The common bacterial toxin hypothesis of sudden infant death syndrome (SIDS) is consistent with the epidemiological features of the condition including the age distribution, seasonal incidence, association with prone sleeping and with exposure to tobacco smoke. The hypothesis is supported by experimental evidence but there are two barriers to its acceptance: the speed of onset does not fit with conventional concepts of an infective process; furthermore, the hypothesis appears to offer a single explanation for what is regarded as a multifactorial disease. Concepts from information theory are used to explore these objections. Complex physiological systems process information and need a high level of redundancy to minimise error. Models show that deleterious mutations in such a system will interact synergistically. Environmental perturbations are most likely to cause failure (sudden death) in systems with several mutations. Models also indicate that mutation rates will pose a limit to the size of the functioning genome and, therefore, increased complexity in evolution depends on using old genes in new combinations rather than the chance appearance of new genes. The idea that we share our genes with the rest of creation (same genes but different combinations) leads to the following conjecture: for every receptor controlling the flow of information across a cell membrane there will be a bacterially coded molecule that can switch it off or on. Based on this premise, bacterial toxaemia could cause sudden death, merely the time it takes for a molecule to associate with or dissociate from its receptor. Regardless of the number of physiological systems involved in SIDS, the age distribution will have a unimodal peak corresponding to the age range during which infant serum IgG reaches its nadir. In this way, the two barriers to the common bacterial toxin hypothesis can be overcome: one explanation but multiple bacteria and toxins acting with variable speed on multiple target systems.

Bacteria↗
PubMed1997

The medical utility of genomics data in neuropsychiatry: mutational genetics versus association genetics.

The long anticipated 'genetic revolution' in neuropsychiatry has yet to have an impact on the practice of clinical medicine. Excitement in the 1980s over major genetic breakthroughs in schizophrenia and manic depression, for example, has been replaced in the late 1990s by the sobering realization that most common neuropsychiatric disorders are multifactorial. Despite considerable effort and resources, no 'causative' genetic variation has been identified that plays a definitive major role in any common neuropsychiatric disorder.

Biological Psychiatry↗
PubMed2002

Intra-tumoral interleukin-6 down-regulation system and genetic mutations of tumor suppressor genes in colorectal carcinoma.

BACKGROUND: The interleukin (IL)-1-IL-6 network, the most potent cascade of pro-inflammatory cytokines, plays an autocrine role in tumor growth. The IL-1-IL-6 network is down-regulated by a phased cytokine inhibitor IL-1 receptor antagonist (ra) and an anti-inflammatory cytokine IL-10. The current study evaluated this down-regulation system in colorectal carcinoma and its relation to the genetic alteration of tumor suppressor genes. METHODS: Seventy-four specimens of primary colorectal carcinoma and normal mucosa were collected to measure tissue concentrations of cytokines. Polymerase chain reaction amplification was performed to investigate the loss of heterozygosity of the microsatellite markers on chromosomes 17p and 18q. RESULTS: The IL-1ra/IL-6 ratio in the carcinoma specimens was lower than ratios in adenomas and normal mucosae and decreased with disease progression. The IL-1ra/IL-6 ratio in early cancers tended to be lower than that in adenomas and normal mucosae. However, the tissue concentrations of IL-1beta and IL-10 were not associated with any clinicopathologic parameters. The tissue IL-1ra concentration correlated with that of IL-6 only in adenomas and early cancers. Immunohistochemically, IL-1ra and IL-6 were localized in the tumor cytoplasm. A reduced tissue IL-1ra/IL-6 ratio in the carcinomas correlated with poor prognosis and was associated with the loss of heterozygosity of the microsatellite markers on chromosomes 18q. CONCLUSIONS: There is an IL-6-IL-1ra network system in colorectal tumors, but this system deteriorates with carcinogenesis and tumor growth. The deterioration of this network system was associated with the allelic loss of a portion of chromosome 18q, reflecting the genetic alteration of tumor suppressor genes.

Adenoma↗
PubMed1995

Identification of a genetic mutation in a family with fructose-1,6- bisphosphatase deficiency.

Fructose-1,6-bisphosphatase deficiency is an inheritable disorder of gluconeogenesis. Sequence analysis of the cDNA of the fructose-1,6-bisphosphatase mRNA isolated from monocytes from a girl with this disease and her consanguineous parents revealed that the patient and her parents were a homozygote and heterozygotes for an insertion of one G residue at G957GGGG961, respectively. This mutation resulted in translation of a truncated enzyme protein, and the mutant protein showed no fructose-1,6- bisphosphatase activity in an overexpression experiment in Escherichia coli. However, this mutation is located in a region of the amino acid sequence which is not well conserved among mammals. A mutagenized clone was prepared from the normal clone. The extents of substitutions and deletions of the amino acid sequence were predicted to be less in the mutagenized protein than in the mutant protein. This mutagenized clone also expressed no fructose-1,6-bisphosphatase activity, although both of two normal clones from control monocytes and a control liver sample expressed an apparently normal level of fructose-1,6-bisphosphatase activity. Thus, this mutation is concluded to be responsible for fructose-1,6-bisphosphatase deficiency in this patient.

Amino Acid Sequence↗
PubMed1991

The NCS3 mutation: genetic evidence for the expression of ribosomal protein genes in Zea mays mitochondria.

A deletion eliminating part of a transcribed region of mitochondrial DNA (mtDNA) has been found in the maize nonchromosomal stripe 3 (NCS3) mutant. This results in the specific loss of a set of three mitochondrial RNAs consisting, in normal plants, of a 4.9 kb transcript, its 1.8 kb intron and the resulting processed mRNA of approximately 2.9 kb. In the NCS3 mitochondrial genome the DNA encoding the putative promoter and 5' end of the affected RNAs is missing. This transcribed region of normal maize mtDNA has been sequenced and the intron splice junction has been determined. The 2.9 kb processed mRNA carries two overlapping open reading frames (ORFs) with predicted amino acid sequences that show similarity to two Escherichia coli ribosomal proteins, S3 (rps3) and L16 (rpl16). The presence of severe stunting and striping in NCS3 plants correlates absolutely with the molecular changes described here. This fact and the impaired ability for mitochondrial protein synthesis by NCS3 plants indicate that one or both of these reading frames are translated to functional ribosomal proteins in normal maize mitochondria.

Amino Acid Sequence↗
PubMedDate not supplied

[A diagnostic analysis of a genetic mutation associated with a deficiency of leukocyte adhesion in cattle].

Bovine leukocyte adhesion (BLAD) is a recessive autosomal disease in Holstein-Friesian cattle caused by point mutation in CD18 gene encoding neutrophil-surface glycoprotein. To determine BLAD carriers, the convenient primers were chosen to amplify the mutant region of gene with the following restriction analysis. A screening program for BLAD has been initiated. Among 190 animals from different Ukrainian farms 6 were heterozygous according to the tested trait, i.e., BLAD deficient. No homozygous BLAD carriers were detected.

Alleles↗
PubMed2002

Carriers of the aspartylglucosaminuria genetic mutation and chronic arthritis.

OBJECTIVE: To ascertain whether being a carrier of an autosomal recessive disease, aspartylglucosaminuria (AGU), predisposes to chronic arthritis, as does AGU disease. METHODS: A group of 173 unrelated patients with rheumatoid arthritis (RA) but with no family members with AGU each gave a blood sample for AGUFin major mutation DNA analysis. A group of 131 AGU carriers who were parents of patients with AGU completed a questionnaire on joint symptoms and gave a blood sample for rheumatoid factor (RF) analysis. Eight RF positive parents with prolonged joint symptoms had a rheumatological evaluation. RESULTS: Six patients (1/28) with RA were carriers of the AGUFin major mutation, whereas the carrier frequency among Finns in general is 1/50 to 1/85. Three AGU carriers had chronic arthritis (2.3%), and 17 (13%) were RF positive; the respective percentages among Finns in general are 1.4% and 5%. CONCLUSION: As for AGU disease, carrier status may also predispose to chronic arthritis.

Adult↗
PubMed1992

Molecular characterization of genetic mutations in human lactate dehydrogenase (LDH) B (H) variant.

We have previously detected a single base substitution of G by A at the Arg codon CGC in exon 4 of the mutant lactate dehydrogenase (LDH) gene, an unstable LDH-B variant (case 1). Here, we use the polymerase chain reaction (PCR) to amplify genomic DNA of two cases (the original case 1 and a new patient, case 2). We were able to confirm that case 1 is homozygous for the mutation, causing a replacement of the conserved Arg by His at residue 173. The resulting LDH-B variant subunit is unstable in vivo. Whereas the mutation in exon 4 was not observed in case 2, a different single base substitution of A by C was detected at the Ser codon AGT in exon 3. This mutation causes a replacement of the conserved Ser by Arg at residue 131. Genomic analysis of the family of case 2 by mismatched PCR showed that the missense mutation was consistent with their biochemical phenotypes. The replacement results in a conformational change of the residues near the Ser, probably because the side chain of Arg is much more bulky than that of Ser. The change may affect the arrangement of the cofactor binding site and result in the loss of enzyme activity. The experimental observations are consistent with computer graphics analyses.

Amino Acid Sequence↗
PubMed1973

Genetic mutations affecting the respiratory electron-transport system of the photosynthetic bacterium Rhodopseudomonas capsulata.

Alternative energy-converting systems permit the nonsulfur purple photosynthetic bacterium Rhodopseudomonas capsulata to grow either with light or (dark) respiration as the source of energy. Respiratory mutants, unable to grow aerobically in darkness, can be readily isolated and the defective step(s) in their respiratory mechanisms can be identified by study of biochemical activities in membrane fragments derived from photosynthetically grown cells. Such analysis of appropriate mutants and revertants permits construction of a model for the respiratory electron-transport system of the wild type. The results obtained indicate differential channeling of electrons derived from succinate and reduced nicotinamide adenine dinucleotide, and are interpreted in terms of a branched electron-transport scheme. The scheme provides a guide for further, more refined analysis of the respiratory mechanisms through biochemical genetic approaches, and several of the mutants isolated can be exploited for investigation of unsolved problems relating to interactions between respiratory and photosynthetic electron transport and the mechanism of inhibition of bacteriochlorophyll synthesis by molecular oxygen.

Antimycin A↗
PubMed2000

CYP2C19 genetic mutations in North Indians.

OBJECTIVES: To identify defective alleles of CYP2C19 (CYP2C19*2 and *3) in North Indians. METHODS: One hundred extensive metabolizers and 21 poor metabolizers of omeprazole were genotyped with respect to CYP2C19*2 and *3 alleles with polymerase chain reaction-based diagnostic tests. RESULTS: Fifty-two extensive metabolizers and six poor metabolizers were homozygous with the CYP2C19*1/*1 genotype, and 48 extensive metabolizers and six poor metabolizers were heterozygous with the CYP2C19*1/*2 genotype. Nine poor metabolizers were homozygous with the CYP2C19*2/*2 genotype. No extensive or poor metabolizers demonstrated the presence of the CYP2C19*3 allele. CYP2C19*2 could explain 43% (9/21) of the poor metabolizers and 57% (24/42) of the defective alleles in poor metabolizers. Allele frequency of CYP2C19*1 and *2 was 0.7 (95% confidence interval of 0.65 to 0.75) and 0.3 (95% confidence interval of 0.25 to 0.35), respectively. Homozygous extensive metabolizers excreted 7.85 +/- 7.6 micromol 5-hydroxyomeprazole in 8 hours, which was 28% more as compared with heterozygous extensive metabolizers who excreted 5.6 +/- 3.6 micromol 5-hydroxyomeprazole in 8 hours (P < .05). CONCLUSIONS: CYP2C19*2 demonstrated allele frequency of 0.3, whereas CYP2C19*3 was absent in North Indians. Because CYP2C19*2 is not able to explain 57% of poor metabolizers, other mutations (CYP2C19*4 to *8) might be present in North Indians. CYP2C19 demonstrated differential evolution in North Indians because the frequency of CYP2C19*2 was similar to that in Oriental subjects, but that of CYP2C19*3 was similar to that in white subjects.

Alleles↗
PubMed1996

Is nasal polyposis in cystic fibrosis a direct manifestation of genetic mutation or a complication of chronic infection?

Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians. It is characterized by abnormal transepithelial sodium and chloride transport. The clinical expressions of the disorder are highly variable including nasal polyposis. Some authors have found that CF children with nasal polyposis form a distinct subgroup of patients within the clinical heterogeneity of the disease with milder gastrointestinal and pulmonary symptoms. The aim of this prospective study was to verify whether the clinical manifestations in CF children with nasal polyposis are different from control CF patients, and to identify any correlation between a phenotype of nasal polyposis and a genotype. Sixty-six CF children, aged 1-25 years, consecutively underwent ENT examination including nasal endoscopy. Twenty-one had nasal polyposis. The remainder formed the control group. There was no statistical difference in the mode and age of presentation of the disease between the two groups. The clinical manifestations (Schwachman and Kulczycki score, colonization by Staphylococcus aureus and Pseudomonas aeruginosa) were comparable between the two groups. We found no statistical difference in the repartition of genotypes between the polyposis and the control groups. Nasal polyposis does not seem to be genetically dependent, but a larger sample of patients is needed to reach an accurate conclusion.

Adolescent↗