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Results for “mutational profiling”

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PubMed1999

Mutation distribution and CYP21/C4 locus variability in Brazilian families with the classical form of the 21-hydroxylase deficiency.

Deficiency of adrenal steroid 21-hydroxylase is the most common form of congenital adrenal hyperplasia and it is considered to be responsible for 90% of the disease. This paper describes for the first time the CYP21B mutation profile in Brazilian patients. We genotyped 41 families with at least one individual affected with the classical form of the 21-hydroxylase deficiency, representing 74 unrelated alleles. In order to characterize different disease-causing alleles, genotyping was performed by Southern blot analysis with three restriction enzymes, allele-specific oligonucleotide hybridization, and allele-specific PCR. Different alleles were distinguished by TaqI C4B RFLP, gene duplications or deletions of either CYP21A + C4B or CYP21B + C4B, large gene conversions and eight mutations that might have been introduced into CYP21B from CYP21A by microconversion events. At least one mutation was detected in 24 different disease-causing alleles, which represents about 85% of the affected alleles in those families. The frequency of the 30 kb deletion of CYP21B was lower than that described for Caucasians. The mutation Sp2 showed the highest frequency (24.65%) and was present mainly in salt-wasting patients, although it was also detected in some patients with the simple virilizing form of the disease. Conversely, I172N showed a frequency of 18.91% and was found mostly in patients affected with the simple virilizing form of the disease. Five other mutations were determined at low frequency, but CL6 was not found in any of the tested alleles.

Adrenal Hyperplasia, Congenital↗

PubMed2004

Molecular profiles as predictive marker for the effect of overall treatment time of radiotherapy in supraglottic larynx squamous cell carcinomas.

BACKGROUND AND PURPOSE: Reduction of the overall treatment time of radiotherapy increases the probability of local tumour control, but it does not benefit all patients. Identification of molecular marker profiles may aid in the selection of patients likely to benefit from accelerated radiotherapy. PATIENTS AND METHODS: Two hundred and nine patients with SCC of the supraglottic larynx received primary radiotherapy in the randomised DAHANCA trials to 66-68 Gy, 2 Gy/fx but with different overall treatment times of 9.5 week, 6.5 week and 5.5 week. Formalin-fixed paraffin embedded tumour slides were assessed by immunohistochemistry for expression of EGFr, E-cadherin, KI-67 and Bcl-2 and the TP53 mutation profile was determined using PCR-amplification, DHPLC and sequencing. The profiles were established using a hierarchical clustering algorithm with a Bayesian information criterion for cluster number optimisation. RESULTS: Full data-set were available for 158 patients and four almost equally sized clusters were identified. One of these clusters differed significantly with respect to local control compared to the other clusters: the cluster (n=36) characterised by wild type TP53, low expression of E-cadherin and Bcl-2, moderate KI-67 and EGFr, was not influenced by a reduction in the overall treatment time (P=0.6) whereas the other clusters showed an increase in local control when the overall treatment time of radiotherapy was reduced. This was also partially seen with disease specific survival as the endpoint. CONCLUSIONS: Molecular marker profiling may aid in the selection of patients that will benefit of a reduction in overall treatment time of radiotherapy in SCC of the supraglottic larynx.

Algorithms↗

PubMed2005

TP53 mutations in salivary gland neoplasms.

Many studies have demonstrated that loss of TP53 gene function has an important role in the genesis of many neoplasms, including salivary gland neoplasms. The purpose of this study was to examine the mutation profile of the TP53 gene in salivary gland neoplasms. Genomic DNA was extracted from paraffin-embedded tissues of pleomorphic adenoma, carcinoma in pleomorphic adenoma, mucoepidermoid carcinoma, adenoid cystic carcinoma and polymorphous low grade adenocarcinoma. Exons 5 to 8 of the TP53 gene were amplified by polymerase chain reaction (PCR) to perform single-stranded conformational polymorphism (SSCP) analysis. Band shifting was observed in exons 5, 6 and 8 in 9 out of 18 neoplasms. The results of this study suggest that mutations in TP53 gene are related to salivary gland neoplasms pathogenesis and that exons 5 and 8 are most frequently involved.

Adenocarcinoma↗

PubMed2000

Novel frameshift mutations in the RP2 gene and polymorphic variants.

Mutations in the RP2 gene located on Xp11.23 are associated with X-linked retinitis pigmentosa (XLRP), a severe form of progressive retinal degeneration which leads to complete loss of vision in affected males. To date, 14 different mutations in the RP2 gene have been reported to cause XLRP, the majority of which lead to a coding frameshift within the gene and predicted truncation of the protein product. We here report two novel frameshift mutations in RP2 identified in XLRP families by PCR-SSCP and direct sequencing, namely 723delT and 796-799del. Four single nucleotide polymorphisms (SNPs) within the coding region of RP2 are also described (105A>T, 597T>C, 844C>T, 1012G>T), the first polymorphisms to be reported within this gene of unknown function, two of which alter the amino acid sequence. The current study extends the XLRP mutation profile of RP2 and highlights non-pathogenic coding sequence variations which may facilitate both functional studies of the gene and analysis of intragenic allelic contribution to the phenotype.

Alternative Splicing↗

PubMed2025

Exploring the Genetic Landscape of Primary Marginal Zone Lymphoma of the Urinary Bladder.

Extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue is the most frequent primary lymphoma of the urinary bladder. Although MZLs from various anatomical sites are often associated with autoimmune disorders, infections, and site-characteristic genetic alterations, the molecular foundations and potential infectious triggers of urinary bladder MZL remain poorly understood. To elucidate the disease etiology and correlation with MZLs arising in other locations, we examined a cohort of 17 cases (11 women and 6 men) diagnosed with primary bladder MZL between 2005 and 2025. Immunohistochemical analysis confirmed the literature, with all samples testing positive for the pan B-cell markers CD20 and CD79a and negative for CD5 (except 1), cyclin D1, and SOX11. Thirteen samples exhibited secretory differentiation and displayed immunoglobulin light chain restriction (9 κ and 4 λ). No gene rearrangements in BCL2, BCL6, BCL10, IRF4, MALT1, and MYC were detected. High-throughput sequencing identified 31 pathogenic/likely pathogenic somatic mutations across 18 genes, with TBL1XR1 (n = 8), MAP2K1 (n = 4), and TNFAIP3 (n = 2) being the most frequently mutated ones. Additionally, all cases included variants of unknown significance. The sample of 1 patient tested positive for Chlamydia trachomatis, human betaherpesvirus 6B, and Epstein-Barr virus. Escherichia coli was detected in 5 samples. We provide compelling evidence that urinary bladder MZL is a point mutation-driven disease rather than gene fusion-driven disease and that E coli is present in approximately one-third of tumor biopsies. These tumors frequently harbor pathogenic mutations in genes encoding components regulating plasma cell differentiation and the pleiotropic MAPK/ERK signaling pathway. TBL1XR1, which was unexpectedly frequently mutated, is generally linked to more aggressive variants of MZL and diffuse large B-cell lymphoma; however, its prognostic significance in urinary bladder MZL remains to be determined. Comparative analysis highlighted partial overlap of urinary bladder MZL mutational profiles with those found in salivary gland MZL.

Humans↗

PubMed1995

Genetic stability and mutant selection in Sabin 2 strain of oral poliovirus vaccine grown under different cell culture conditions.

Mutations that consistently accumulated in the attenuated Sabin 2 strain of poliovirus during propagation in cell cultures were identified by sequence heterogeneity assay and quantified by mutant analysis by PCR and restriction enzyme cleavage (MAPREC). Eight additional sites previously identified in stool isolates were also examined by MAPREC in the virus passages. The pattern of selectable mutations and the rate of their accumulation depended on the type and confluence of the cell culture and the temperature of virus growth. Five unstable genomic sites were identified in Sabin 2 virus passaged 10 times at 34 degrees in African green monkey kidney (AGMK) cells, with the mutations accumulating in the range 1 to 24%. Accumulation of these mutations did not appear to result in a loss of attenuated phenotype since the virus passaged under these conditions passed the monkey neurovirulence test (MNVT). The content of the 481-G revertant known to be related to neurovirulence in monkeys did not increase. Thus, our results suggest that upon growth of Sabin 2 virus in AGMK cells at 34 degrees, the key determinant(s) of attenuation remained stable, and the mutations that occurred did not affect monkey neurovirulence. In virus passaged 10 times at 37 degrees in AGMK cells, 4 unstable genomic sites were identified, in some of them accumulating up to 12% of the mutants. This virus sample severely failed the MNVT. Virus passaged in Vero cells at 34 and 37 degrees accumulated mutants at 7 and 14 genomic sites, respectively, including 481-G in both cases, with almost complete substitution of the original nucleotides at some of the sites. We tested 44 commercial monopools of Type 2 OPV and found out that all of them contained 481-G revertants in the range 0.4-1.1%. An increase in the 481-G revertants in passaged viruses to the level of 4% and above correlated with failure of these samples by the MNVT. Since the pattern of selectable mutations differed in viruses grown in the two cell cultures used in this study, specific mutation profiles should be determined for each cell substrate used for vaccine production to assess manufacturing consistency.

Amino Acid Sequence↗

PubMed2006

Mutation analysis of Gaucher disease patients in Taiwan: high prevalence of the RecNciI and L444P mutations.

Gaucher disease, the most prevalent lysosomal storage disease characterized by a remarkable degree of clinical variability, results from deleterious mutations in the beta-glucosidase gene. Although >200 mutations in the gene for human beta-glucosidase have been described, most genotype/phenotype studies have focused on screening for a few common mutations. In the present study, whole gene sequencing analysis was performed. We sequenced eight patients with type 1, five patients with type 2, and six patients with type 3 Gaucher disease in Taiwan. A total of 37 Gaucher chromosome were identified. The detection rate is 97%. For types 1 and 3 Gaucher disease, 1448 T > C (L444P) account for 53.5% Gaucher chromosome and the recombinant allele [1448 T > C, 1483 T > G, 1497 G > C] (RecNciI) has 25% prevalence rate among those patients. For type 2 Gaucher disease, all five patients carry L444P mutation, and RecNciI is found in two of the six patients. Because L444P is also present in the RecNciI mutation, all the patients in this study have a L444P mutation in their Gaucher chromosomes. The third most common mutation of type 1 Gaucher disease is 475 C > T (R120W). L444P homozygote and R120W/RecNciI genotypes are associated with non-neuronopathic Gaucher disease. RecNciI is related to neuronopathic disease, while R120W is represented as a mild mutation in Taiwan. The mutation profile of Gaucher disease in Taiwan is limited. Only four different alleles were identified in types 1 and 3 as well as in type 2 Gaucher disease.

Adolescent↗

PubMed2026

Clinical, epidemiological, and genomic evidence on mpox in mainland China, 2022-2025: a scoping review.

BACKGROUND: Since 2022, mpox has expanded globally with sustained human-to-human transmission and increasing evidence of MPXV genomic diversification. In mainland China, mpox evidence has accumulated rapidly, but clinical, epidemiological, and genomic findings remain fragmented. METHODS: We conducted a scoping review of PubMed, CNKI, and WanFang databases up to March 2, 2026, and integrated literature-derived evidence with public MPXV sequences from GenBank, GenBase, and GISAID. Literature-derived data were used to map clinical-epidemiological characteristics, study-level genomic evidence, sequencing coverage, and reported lineage distribution. Curated public MPXV sequences were used for phylogenetic reconstruction, amino acid mutation profiling, and APOBEC-like substitution analysis. RESULTS: Fifty-eight studies were included: 32 addressed clinical or epidemiological evidence only, 25 addressed genomic evidence only, and one contributed to both domains. Fourteen hospital-based studies summarized 951 cases, showing that reported cases were concentrated among young adult men, with frequent MSM exposure (798/897, 89.0%; 95% CI 86.7-90.9%) and HIV co-infection (469/951, 49.3%; 95% CI 46.1-52.5%). Public sequence curation identified 231 unique mainland China MPXV sequences, of which 230 were used for phylogenetic and mutation analyses. Literature-based genomic evidence comprised 26 genomic studies, 37 study-level genomic records, and 31 reported-case units, including 414 sequenced cases among 530 reported cases (78.1%; 95% CI 74.4-81.4%). Clade IIb predominated among sequenced cases (412/414, 99.5%; 95% CI 98.3-99.9%), with C.1.1 and C.1 most frequently represented. Within the available dataset, public genomes represented multiple lineages and were unevenly distributed across regions and time. Mutation analysis revealed dispersed amino acid variation and a predominance of G>A and C>T transitions (73.0%). After collapsing recurrent substitutions to unique genomic sites, the proportion of G>A/C>T transitions decreased to 35.8% and further to 17.8% under a strict APOBEC3 motif definition, indicating that the observed mutation spectrum includes both shared lineage-associated substitutions and sequence-context-based APOBEC-like patterns. CONCLUSION: Available evidence indicates multi-lineage MPXV circulation and in mainland China, but interpretation remains constrained by uneven sequencing and lack of individual-level clinical-genomic linkage. Integrated genomic surveillance and standardized data linkage are needed to better characterize MPXV transmission and evolution.

APOBEC‑like substitutions↗

PubMed2026

Selective Inhibition of DNA Polymerase Proofreading: A Metabolic-Fidelity Mechanism Explains Agent Orange-Associated Myelodysplasia.

We performed a focused review to better understand the pathogenesis of Agent Orange (AO)-associated myelodysplastic syndrome (MDS). We first examined the mechanisms underlying conventional (de novo) MDS, a clonal hematopoietic neoplasm that typically develops in later life, and integrated these findings with our recent analysis of obesity-associated carcinogenesis. Accordingly, we propose that genomic instability in de novo MDS results from selective inhibition of the DNA polymerase proofreading exonuclease. In obesity-associated carcinogenesis, impaired AMP-activated protein kinase (AMPK) activity disrupts mitochondrial ATP production, increasing intracellular AMP concentrations. Elevated AMP selectively inhibits the proofreading exonuclease while preserving polymerase activity, allowing replication errors to escape correction and become fixed as somatic mutations. Molecular studies demonstrate that AO-associated MDS exhibits essentially the same mutational profile as de novo disease despite arising after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in young, otherwise healthy military personnel. Because TCDD is highly lipophilic, it accumulates in adipose tissue and is released slowly over decades, producing sustained mitochondrial dysfunction, reduced ATP synthesis, and chronic elevation of intracellular AMP. We propose that this metabolic disturbance converges on the same endpoint-selective inhibition of the proofreading exonuclease-thereby promoting mutagenesis and clonal evolution. Recent studies further strengthen the central role of proofreading by demonstrating that many mutations, including many found in MDS, previously attributed to spontaneous cytosine deamination, instead arise from DNA polymerase misincorporation of thymidine opposite cytosine, particularly at CpG dinucleotides, emphasizing the critical importance of fully active proofreading in preventing such misincorporations from accumulating as mutations in the genome of the cell.

AMP↗

PubMed2003

The molecular basis of phenylketonuria in Lithuania.

We report the spectrum of phenylalanine hydroxylase (PAH) gene mutations in patients with phenylketonuria (PKU) residing in Lithuania. A total of 184 independent chromosomes was investigated. R408W mutation was first analysed through restriction enzyme digestion of exon 12. The remaining uncharacterised PKU chromosomes were analysed by scanning the whole coding sequence of PAH gene by multiplex 'broad range' denaturing gradient gel electrophoresis. Mutations were identified by fluorescent automated sequencing or by restriction enzyme digestion analysis if an abnormal DGGE pattern was recognised. 21 different mutations were identified for 175 PKU chromosomes, with a mutation detection rate of 95%. The most common ones were R408W (73.5% chromosomes) and R158Q (7.0% chromosomes) whereas the remaining mutations appeared to be rare (relative frequencies 0.5%-2%). The high mutation detection rate obtained is an evidence of the efficiency of PAH genetic testing achieved in Lithuania. Moreover, the definition of the PKU mutation profile in the Lithuanian population will allow to perform a genotype-phenotype correlation study thus making feasible genotyped-based prediction of the biochemical phenotype in newborns with hyperphenylalaninemia. This may be useful for refining diagnosis and anticipating dietary requirements.

Amino Acid Substitution↗

PubMed2006

Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil.

BACKGROUND: Adefovir dipivoxil (ADV) is a potent nucleotide analogue against both the wild-type and lamivudine (LMV) resistant hepatitis B virus (HBV). The cumulative incidence of ADV resistant mutations in the nucleoside/-tide treatment naive chronic hepatitis B patient (CHB) at weeks 48, 96, and 144 was 0, 0.8-3%, and approximately 5.9%, respectively. AIMS: The aim of this study was to characterise the genotypic and phenotypic mutation profiles to ADV in 67 LMV resistant CHB patients who were treated with ADV. METHODS: Serum HBV DNA was quantified by real time polymerase chain reaction. The ADV mutant was detected using matrix assisted laser desorption/ionisation time of flight mass spectrometry based genotyping assays, termed restriction fragment mass polymorphism (RFMP). RESULTS: RFMP analysis revealed that a total of 11 amino acid substitutions developed in the rt domain of the HBV polymerase in nine patients. The cumulative incidence of genotypic ADV resistance at months 12 and 24 was 6.4% and 25.4%, respectively. The rtA181V, rtN236T, and rtA181T mutations were detected in five, four, and two of the 67 patients at treatment months 12-17, 3-19, and 7-20, respectively. Serial quantification of serum HBV DNA revealed that two patients with the rtA181V mutation, with or without the rtN236T mutation, and one patient with the rtA181T mutation displayed HBV DNA rebound. CONCLUSION: Emergence of the ADV mutation in LMV resistant patients who are treated with ADV appeared to present earlier and more frequently than was reported in previous studies on nucleoside/-tide treatment naive patients.

Adenine↗

PubMed2000

Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6000 samples.

OBJECTIVE: To evaluate in HIV-1 the extent of phenotypic and genotypic antiretroviral drug resistance and cross-resistance towards the protease inhibitors (PIs) saquinavir, ritonavir, indinavir and nelfinavir among a set of patient samples originating from European and US routine clinical practice and submitted for phenotypic drug resistance testing and/or genotypic analysis. The mutational pattern(s) underlying both resistance and cross-resistance to PIs was investigated. METHOD: Over 6000 patient isolates with plasma viral load greater than 1000 copies/ml plasma were analysed. Phenotypic resistance was evaluated by a recombinant virus assay. Phenotypic resistance is expressed as the fold-increase of the 50% inhibitory concentration (IC50) value of a compound for a patient-derived recombinant virus isolate compared with that for a wild-type laboratory virus. Genotypic analysis is reported as amino acid changes at positions in the HIV-1 protease compared to a wild-type reference. RESULTS: Phenotypic resistance to any single PI was observed in 17 to 25% of the clinical isolates investigated. Phenotypic cross-resistance among PIs (> 10-fold increase in IC50 value) was detected in 59 to 80% of the samples resistant (> 10-fold increase in IC50 value) to at least one PI. The prevalent mutations in PI-resistant isolates involved substitutions at codons 10, 36, 46, 54, 71, 77, 82 and 90. The most frequent mutational pattern in samples with PI cross-resistance involved combined substitutions at positions 10 and 90, extended with substitutions at positions 54, 71, 77, 82 or 84. CONCLUSIONS: Extensive use of first-generation PIs leads to the emergence of HIV-1 isolates possessing cross-resistance to all members of this class. Identification of particular mutational profiles among these isolates may assist in the design of new generation inhibitors with specific activity against protease-mutant HIV strains.

Amino Acid Substitution↗

PubMed2026

Prognostic significance of DNA damage response-related markers in esophageal squamous cell carcinoma using machine learning approaches.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) lacks reliable prognostic biomarkers. Homologous recombination deficiency (HRD) has been implicated in genomic instability across multiple cancers, but its prognostic significance in ESCC remains unexplored. This study aimed to evaluate HRD score as a prognostic biomarker and develop a machine learning-based predictive model for ESCC. METHODS: Transcriptomic and clinical data from 78 ESCC patients were obtained from The Cancer Genome Atlas (TCGA) and randomly split into training (70%) and test (30%) cohorts. Prognostic models were constructed using 112 machine learning algorithm combinations based on DNA damage response (DDR)-related genes. Gene set enrichment analysis (GSEA), somatic mutation profiling, and immune cell infiltration estimation via CIBERSORT were performed to characterize HRD-associated molecular features. RESULTS: High HRD scores were significantly associated with poorer overall survival (P<0.05). Among 112 algorithm combinations, the survival support vector machine (Survival-SVM) model demonstrated optimal performance [training concordance index (C-index): 0.741; test C-index: 0.708], identifying six hub genes: PARP1, MBD4, TELO2, NSMCE3, SMUG1, and BABAM1. A nomogram incorporating risk score (RS) and clinical variables achieved strong predictive accuracy for 1- to 3-year survival [area under the curve (AUC) >0.7]. High-HRD tumors exhibited distinct mutational patterns (TP53 and TTN) and enriched glutathione metabolism and cytochrome P450 pathways. Immune infiltration analysis revealed significant differences in plasma cell and neutrophil infiltration between risk groups (P<0.05), suggesting HRD-associated immune microenvironment remodeling. CONCLUSIONS: We developed a novel HRD-based prognostic model incorporating six DDR-related genes that demonstrates robust predictive performance in ESCC. HRD score is identified as an independent prognostic factor associated with genomic instability, immune microenvironment alterations, and clinical outcomes. These findings provide a theoretical basis for personalized treatment strategies, including potential applications of PARP inhibitors and immunotherapy in ESCC.

Esophageal squamous cell carcinoma (ESCC)↗

PubMed1998

Human propionyl-CoA carboxylase beta subunit gene: exon-intron definition and mutation spectrum in Spanish and Latin American propionic acidemia patients.

Propionyl-CoA carboxylase (PCC) is a mitochondrial biotin-dependent enzyme composed of an equal number of alpha and beta subunits. Mutations in the PCCA (alpha subunit) or PCCB (beta subunit) gene can cause the inherited metabolic disease propionic acidemia (PA), which can be life threatening in the neonatal period. Lack of data on the genomic structure of PCCB has been a significant impediment to full characterization of PCCB mutant chromosomes. In this study, we describe the genomic organization of the coding sequence of the human PCCB gene and the characterization of mutations causing PA in a total of 29 unrelated patients-21 from Spain and 8 from Latin America. The implementation of long-distance PCR has allowed us to amplify the regions encompassing the exon/intron boundaries and all the exons. The gene consists of 15 exons of 57-183 bp in size. All splice sites are consistent with the gt/ag rule. The availability of the intron sequences flanking each exon has provided the basis for implementation of screening for mutations in the PCCB gene. A total of 56/58 mutant chromosomes studied have been defined, with a total of 16 different mutations detected. The mutation spectrum includes one insertion/deletion, two insertions, 10 missense mutations, one nonsense mutation, and two splicing defects. Thirteen of these mutations correspond to those not described yet in other populations. The mutation profile found in the chromosomes from the Latin American patients basically resembles that of the Spanish patients.

Amino Acid Substitution↗

PubMed1995

Analysis of VH gene expression in CD5+ and CD5- B-cell chronic lymphocytic leukemia.

In contrast to highly mutated follicular lymphomas and multiple myelomas, chronic lymphocytic leukemias (CLLs) frequently express VH genes in germline configuration. It is currently unclear whether this difference is related to the expression of CD5 or to the differentiation stage of the B cell when malignant transformation occurs. We have studied the VH sequence of 11 cases of CD5- B-CLL to address the question whether CD5- B-CLL are derived from naive pregerminal B cells (low mutation pattern) or from germinal center-derived memory B cells (high mutation pattern). Among the 12 detected rearrangements (2 distinct rearrangements in 1 case) VH1 family was found in 2, VH2 in 2, VH3 in 4, and VH4 in 4. Nine different VH genes were detected among the 12 rearrangements, including 2 cases expressing V1-69 (51p1) and 1 case expressing V4-39 (VH4.18), previously reported to be overexpressed in CD5+ B-CLL. A higher mutation pattern, following a random distribution, was observed when compared with classical CD5+ B-CLL. However, as reported in normal B cells, these results appeared to be related to membrane Ig phenotype (less mutations in membrane mu delta-expressing forms in leukemias expressing exclusively membrane mu). Overall, the differences found when comparing the mutational profile with classical CD5+ B-CLL were not clearcut and might be explained more by the membrane isotype (mu v mu delta) than by CD5 expression.

Aged↗

PubMed2001

International perspectives on antiretroviral resistance. Resistance to protease inhibitors.

The availability of protease inhibitors (PIs) and their combination with nucleoside reverse transcriptase inhibitors marked the passage of antiretroviral therapy (ART) from potential for control to effective suppression and thus substantially reduced rates of morbidity and mortality related to HIV. Even so, what was first hoped to be an immutable HIV DNA treatment target has proved to be prone to resistance mutations, with substitutions identified at more than 20 amino acid sites, which reduces PI susceptibility and increases resistance to treatment. The mutation patterns associated with each PI have been defined, and have been observed to occur at one of two locations: at or near the active site, or in the substrate cleavage site. The natural history of PI resistance has been extensively studied, and the genetic and cellular pathways are described in detail in this article. In addition, cross-resistance among PIs is now recognized to be fairly extensive, although the degree of cross-resistance varies with the number of mutations and the variants selected by drug pressure. Thus, it is still possible to salvage a response with another PI after a first regimen with another PI has failed. The extensive basic science and clinical experience with PIs in the fight against HIV are reviewed in this article, which provides data on resistance-mutation profiles, cellular resistance mechanisms, viral fitness studies, and clinical outcome trials with various first-line and subsequent regimens that contain PIs. It is hoped that the information provided will guide physicians in best using PIs as part of a logical and successful ART strategy.

Amino Acid Substitution↗

PubMed2000

pncA mutations as a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis: spread of a monoresistant strain in Quebec, Canada.

Pyrazinamide (PZA) is an important first-line tuberculosis drug that is part of the currently used short-course tuberculosis chemotherapy. PZA is a prodrug that has to be converted to the active form pyrazinoic acid by pyrazinamidase (PZase) activity, encoded by the pncA gene of Mycobacterium tuberculosis, and loss of PZase activity is associated with PZA resistance. To further define the genetic basis of PZA resistance and determine the frequency of PZA-resistant strains having pncA mutations, we sequenced the pncA gene from a panel of 59 PZA-resistant clinical isolates from Canada, the United States, and Korea. Two strains that did not contain pncA mutations and had positive PZase turned out to be falsely resistant. Three PZase-negative strains (MIC, >900 microgram of PZA per ml) and one PZase-positive strain (strain 9739) (MIC, >300 microgram of PZA per ml) did not have pncA mutations. The remaining 53 of the 57 PZA-resistant isolates had pncA mutations, confirming that pncA mutation is the major mechanism of PZA resistance. Various new and diverse mutations were found in the pncA gene. Interestingly, 20 PZA-monoresistant strains and 1 multidrug-resistant isolate from Quebec, Canada, all had the same pncA mutation profile, consisting of an 8-nucleotide deletion and an amino acid substitution of Arg140-->Ser. Strain typing indicated that these strains are highly related and share almost identical IS6110 patterns. These data strongly suggest the spread of a PZA-monoresistant strain, which has not previously been described.

Amidohydrolases↗

PubMed2006

Antimicrobial susceptibility and molecular determinants of quinolone resistance in Neisseria gonorrhoeae isolates from Shanghai.

OBJECTIVES: To determine the antimicrobial susceptibility of Neisseria gonorrhoeae from Shanghai and to type the quinolone resistance-determining regions (QRDRs) of ciprofloxacin-resistant isolates. METHODS: N. gonorrhoeae isolates (n = 159) were consecutively collected from male patients in Shanghai and examined for their antimicrobial susceptibilities to penicillin, tetracycline, ciprofloxacin, spectinomycin and ceftriaxone. The mutation profiles of the QRDRs of gyrA and parC were determined for 103 isolates including one susceptible isolate and one isolate with intermediate levels of susceptibility to ciprofloxacin. RESULTS: High percentages of the 159 isolates were resistant to ciprofloxacin (98.7%), penicillin (93.1%) and tetracycline (56.5%). Penicillinase-producing N. gonorrhoeae (PPNG, 37.8%) or penicillinase-producing/tetracycline-resistant N. gonorrhoeae (PP/TRNG, 13.8%) accounted for 51.6% of the isolates. Chromosomal resistance to penicillin was observed in 41.5% of the isolates. Tetracycline resistance was noted in 56.5% of the isolates with 20.1% carrying plasmid-mediated resistance and 36.4% being chromosomally resistant. All isolates were susceptible to ceftriaxone and spectinomycin, although a trend to decreased susceptibility was noted. QRDR mutations were observed in the 101 ciprofloxacin-resistant isolates and the one ciprofloxacin-intermediate isolate, in contrast to the ciprofloxacin-susceptible isolate tested. Mutations in the QRDRs comprised four predominant (65.0% of the 103 isolates) patterns of a total of 19 patterns. Mutations in parC were significantly associated with higher MICs of ciprofloxacin. CONCLUSIONS: Spectinomycin and ceftriaxone are currently recommended for the treatment of gonorrhoea in Shanghai. Although the present study indicates that these antimicrobials should remain effective, the identification of isolates with decreased susceptibility underscores the importance of ongoing antimicrobial susceptibility surveillance to monitor and respond to the emergence of resistant isolates.

Anti-Infective Agents↗