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At least 487 records · Page 27Linked to original sources
PubMed2001

Low-density lipoprotein receptor gene mutation analysis and clinical correlation in Belgian hypercholesterolaemics.

It is generally believed that patients with familial hypercholesterolaemia (FH) have a higher cardiovascular risk than hypercholesterolaemics without a defect in the low-density lipoprotein receptor (LDLR) gene. However, no conclusive evidence to support this view has yet been presented. We investigated this aspect in Belgian hyperlipidaemics as part of a comprehensive effort to determine the impact of FH in this population. DNA samples of 98 unrelated Belgian patients with a family history of autosomal dominant hypercholesterolaemia were screened for mutations in the LDLR gene, after exclusion of known mutations causing familial defective apolipoprotein B-100 (FDB). Eight of the 22 distinct LDLR gene mutations identified in 27 subjects have not previously been described in other populations. As expected, the mutation-positive patients had a significantly worse lipid profile than the mutation-negative subjects (p<0.05), but this did not correlate with clinical cardiovascular status. In conclusion, the presence of a mutation in the LDLR gene was not a reliable predictor of cardiovascular risk in the hyperlipidaemic subjects included in this study. However, it is possible that prolonged exposure to the high levels of LDL cholesterol in genetically proven FH patients will in future cause a higher incidence of coronary heart disease. Our data may reflect the genetic heterogeneity of inherited hypercholesterolaemia, recently shown to be caused by several major genes.

Adolescent↗
PubMed2005

Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer.

We report the association of CDH1/E-cadherin mutations with cleft lip, with or without cleft palate (CLP), in two families with hereditary diffuse gastric cancer (HDGC). In each family, the CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing the extracellular cadherin repeat domains involved in cell-cell adhesion. Such transcripts might encode mutant proteins with trans-dominant negative effects. We found that CDH1 is highly expressed at 4 and 5 weeks in the frontonasal prominence, and at 6 weeks in the lateral and medial nasal prominences of human embryos, and is therefore expressed during the critical stages of lip and palate development. These findings suggest that alteration of the E-cadherin pathway can contribute to human clefting.

Adult↗
PubMed2001

Tau proteins with frontotemporal dementia-17 mutations have both altered expression levels and phosphorylation profiles in differentiated neuroblastoma cells.

The inherited form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) has been attributed to mutations in the tau gene. Pathologically, affected FTDP-17 brains share tau aggregates with other tauopathies, the most common being Alzheimer's disease. FTDP-17 mutations may therefore affect tau function leading to tau aggregation and cell loss. Interaction of tau with microtubules is thought to be regulated by phosphorylation. Investigating FTDP-17 mutations transiently expressed as enhanced green fluorescent protein (EGFP)-tagged proteins for the first time in differentiated neuronal cells, we found that two out of three missense mutations showed surprisingly decreased phosphorylation at the pathologically relevant S202/T205 site, mutant EGFP-tau being completely dephosphorylated in most cells. Moreover, phosphorylation at the S396/S404 site was moderately decreased for all mutant isoforms. Although microtubule integrity was not affected, with all mutants tested we demonstrated an increase in cellular tau protein level, some of which is microtubule-bound. Further enhancing this EGFP-tau accumulation by inhibition of tau degradation resulted in the previously less phosphorylated mutant EGFP-tau becoming highly phosphorylated. We conclude that the missense tau mutations primarily result in an excess of neuronal tau, which may interfere with important cellular functions such as axonal transport.

Alzheimer Disease↗
PubMed1999

The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominantly inherited disease of the cardiac sarcomere, caused by numerous mutations in genes encoding protein components of this structure. Mutation carriers are at risk of sudden cardiac death, mostly as adolescents or young adults. The reproductive disadvantage incurred may explain both the global occurrence of diverse independent HCM-associated mutations and the rare reports of founder effects within populations. We have investigated whether this holds true for two South African subpopulations, one of mixed ancestry and one of northern-European descent. Previously, we had detected three novel mutations-Ala797Thr in the beta-myosin heavy-chain gene (betaMHC), Arg92Trp in the cardiac troponin T gene (cTnT), and Arg645His in the myosin-binding protein C gene (MyBPC)-and two documented betaMHC mutations (Arg403Trp and Arg249Gln). Here we report three additional novel mutations-Gln499Lys in betaMHC and Val896Met and Deltac756 in MyBPC-and the documented betaMHC Arg719Gln mutation. Seven of the nine HCM-causing mutations arose independently; no conclusions can be drawn for the remaining two. However, the betaMHC Arg403Trp and Ala797Thr and cTnT Arg92Trp mutations were detected in another one, eight, and four probands, respectively, and haplotype analysis in families carrying these recurring mutations inferred their origin from three common ancestors. The milder phenotype of the betaMHC mutations may account for the presence of these founder effects, whereas population dynamics alone may have overridden the reproductive disadvantage incurred by the more lethal, cTnT Arg92Trp mutation.

Cardiomyopathy, Hypertrophic↗
PubMed2001

Molecular pathologic analysis enhances the diagnosis and management of Muir-Torre syndrome and gives insight into its underlying molecular pathogenesis.

The Muir-Torre syndrome (MTS) is an autosomal dominantly inherited disorder, characterized by visceral malignancies and sebaceous skin lesions. In a subset of MTS families the disease is due to an underlying DNA mismatch-repair defect. We have identified a MTS family whose spectrum of reported neoplasia included adenocarcinomas of numerous gastrointestinal sites, carcinomas of the endometrium, ovary and breast, papillary transitional cell carcinoma of the ureter, a range of cutaneous tumors, as well as keratoacanthomas. All tumors were tested for microsatellite instability and immunohistochemically stained for expression of MLH1 and MSH2 proteins. All tumors were found to be microsatellite unstable and lacking in MSH2 protein expression. The subsequent mutation detection focused on hMSH2, and a germline mutation was identified (CAA-->TAA, Gln-->STOP, codon 337). This mutation was subsequently found in a family member with a single skin lesion only. We propose that the combination of immunohistologic and microsatellite instability analysis can be exploited to screen individuals with characteristic skin lesions even before development of visceral tumors and to direct the subsequent germline mutation search. The profile of microsatellite instability and the genes rendered dysfunctional differed between tumor samples, suggesting that the molecular pathogenesis varied between lesions, despite a common germline mutation.

Adult↗
PubMed2003

Audiological profile of the prevalent genetic form of childhood sensorineural hearing loss due to GJB2 mutations in northern Greece.

The present study describes the audiological profile of genetic hearing loss resulting from GJB2 mutations in northern Greece, as this represents the most frequent single cause of childhood sensorineural hearing loss. The 35delG mutation in homozygosity was detected in 27 of 107 patients (25.2%). The audiological profile is that of a profound or severe sensorineural hearing loss, with a sloping or flat configuration of the audiogram, mostly symmetrical, non-progressive and affecting more the higher frequencies. This profile underlines the importance of early identification and genetic family counseling leading to the future possibility of prevention of deafness.

Adolescent↗
PubMed2005

Machine learning approaches for phenotype-genotype mapping: predicting heterozygous mutations in the CYP21B gene from steroid profiles.

OBJECTIVE: Non-linear relations between multiple biochemical parameters are the basis for the diagnosis of many diseases. Traditional linear analytical methods are not reliable predictors. Novel nonlinear techniques are increasingly used to improve the diagnostic accuracy of automated data interpretation. This has been exemplified in particular for the classification and diagnostic prediction of cancers based on expression profiling data. Our objective was to predict the genotype from complex biochemical data by comparing the performance of experienced clinicians to traditional linear analysis, and to novel non-linear analytical methods. DESIGN AND METHODS: As a model, we used a well-defined set of interconnected data consisting of unstimulated serum levels of steroid intermediates assessed in 54 subjects heterozygous for a mutation of the 21-hydroxylase gene (CYP21B) and in 43 healthy controls. RESULTS: The genetic alteration was predicted from the pattern of steroid levels with an accuracy of 39% by clinicians and of 64% by linear analysis. In contrast, non-linear analysis, such as self-organizing artificial neural networks, support vector machines, and nearest neighbour classifiers, allowed for higher accuracy up to 83%. CONCLUSIONS: The successful application of these non-linear adaptive methods to capture specific biochemical problems may have generalized implications for biochemical testing in many areas. Nonlinear analytical techniques such as neural networks, support vector machines, and nearest neighbour classifiers may serve as an important adjunct to the decision process of a human investigator not 'trained' in a specific complex clinical or laboratory setting and may aid them to classify the problem more directly.

Adult↗
PubMed2002

Refined mapping of Naegeli-Franceschetti- Jadassohn syndrome to a 6 cM interval on chromosome 17q11.2-q21 and investigation of candidate genes.

Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis are autosomal dominant ectodermal dysplasias characterized by the absence of dermatoglyphics, reticulate hyper pigmentation of the skin, hypohidrosis, and heat intolerance. Palmoplantar keratoderma, nail dystrophy, and enamel defects are common in Naegeli-Franceschetti-Jadassohn syndrome, whereas diffuse alopecia is only seen in dermatopathia pigmentosa reticularis. We studied a large Swiss family with Naegeli-Franceschetti-Jadassohn syndrome originally described by Naegeli in 1927 and assessed linkage to chromosome 17q, which was proposed to harbor the Naegeli-Franceschetti-Jadassohn syndrome gene. Our results considerably narrow the Naegeli-Franceschetti-Jadassohn syndrome gene region from 27 cM to 6 cM flanked by D17S933 and D17S934 with a maximum multipoint LOD score of 2.7 at marker locus D17S800. In addition, we studied a small family with dermatopathia pigmentosa reticularis, and our linkage data suggest that dermatopathia pigmentosa reticularis may map to the same chromosomal region. The Naegeli-Franceschetti-Jadassohn syndrome critical interval spans approximately 5.4 Mb and contains a minimum of 45 distinct genes. We scrutinized 13 new prime candidates in addition to five genes previously examined, established the genomic organization of 10 of these genes, and excluded all of them by mutation analysis. Moreover, we identified a cDNA (KRT24) encoding a new keratin protein that bears high similarity to the type I keratins and displays a unique expression profile. No pathogenic mutations were identified in this novel gene either, however. In summary, our results substantially refine the Naegeli-Franceschetti-Jadassohn syndrome region and will aid in identifying a gene that is critical for ontogenesis of multiple ectodermal tissues.

Amino Acid Sequence↗
PubMed2005

Predicting the oncogenicity of missense mutations reported in the International Agency for Cancer Research (IARC) mutation database on p53.

Many mutation databases, comprising thousands of reported mutations, are available. Often the clinical significance of the reported mutations is unknown. In this study we developed an algorithm that allows prediction of the clinical significance of missense mutations reported in a mutation database. Nonsense mutations are used as a referent group for this assessment. We used the International Association for Research on Cancer (IARC) mutation database on TP53 to implement the algorithm. First, on the basis of published data [Nachman MW, Crowell SL. 2000. Genetics 156:297-304], we ascribed mutation rates to every single nucleotide substitution (SNS) in the core domain of the TP53 gene. Second, for every possible SNS we computed the expected number of missense mutations, under the assumption that missense mutations are as oncogenic as nonsense ones. The natural logarithm of the ratio of the observed to the expected number of missense mutations (LR) was used as a quantitative measure of oncogenicity (i.e., the ability of a mutation to produce cancer). We estimated the relative oncogenicity of all missense mutations reported in the IARC p53 mutation database, and constructed a profile of oncogenicity of the missense mutations along the DNA-binding region of p53.

Algorithms↗
PubMedDate not supplied

Limited role of TP53 and TP53-related genes in myxoid liposarcoma.

AIMS: Circumstantial evidence suggests that genetic changes may lead to tumor progression within the myxoid liposarcoma tumors (MLTs) carrying non-random chromosomal translocation t(12;16). METHODS: To address this subject an immunophenotypic analysis, applying antibodies against proteins encoded by TP53, MDM2 and CDK4 genes, complemented by molecular analysis of eight suitable cases, was performed on 104 consecutive cases. Chromosomal translocations were assessed either by cytogenetic analysis or by RT-PCR in 9 suitable cases and chimeric transcripts were found in all cases but two pleomorphic liposarcomas. RESULTS: Based on immunophenotyping and tumor site, the case material consisted of three groups. The first one was made up of 92 non-retroperitoneal cases carrying a null p53, mdm2, cdk4 immunophenotype, which remained unchanged over the time of recurrences and along the gamut of histologic subtypes. The second group was represented by five p53+, mdm2-, cdk4- non-retroperitoneal cases, 4 of which were further analysed by PCR-SSCP for p53 mutation. The immunophenotypic profile of these cases, complemented by the molecular findings, supported a role of TP53 in tumor progression in three high-grade MLTs. The third group, consisting of 7 retroperitoneal cases, showed a heterogeneous immunophenotype, sharing immunophenotypic and molecular features with the well-differentiated/evoluted (dedifferentiated) liposarcoma group. CONCLUSIONS: TP53 mutations seem to play a role in tumor progression in a few cases of MLTs (2.8%) showing more aggressive histologic characteristics. The unexpected finding that a number of retroperitoneal LMTs display the immunophenotypic profile of the well differentiated/evoluted (dedifferentiated) liposarcomas, deserves further investigation.

DNA Mutational Analysis↗
PubMed2026

Risk factors for lung metastasis in children and adolescent patients with papillary thyroid cancer: A retrospective cohort study.

BACKGROUND: Pediatric papillary thyroid cancer (pPTC) exhibits a higher incidence of lung metastasis (LM) compared to its adult counterpart. This study supplements the gap in pediatric management guidelines by exploring factors associated with LM in pPTC and characterizing relevant genetic alterations. METHODS: We retrospectively analyzed pPTC patients under 20 years who underwent initial surgery at our center between December 2008 and December 2022. Clinicopathological features, treatment approaches, outcomes, and target-gene sequencing were reviewed to identify risk factors and genetic variations. RESULTS: Among 114 pPTC cases, 17 developed LM. Risk factors associated with LM included younger age, male gender, larger tumor size, multifocality, extrathyroidal extension, lymphatic invasion, and the number of metastatic lymph nodes (NMLNs), with NMLNs&#x2009;>&#x2009;14 identified as an independent predictor (OR&#x2009;=&#x2009;18.20, p&#x2009;=&#x2009;0.037). Treatment responses with radioiodine related to postoperative stimulated thyroglobulin (sTg) levels (p&#x2009;=&#x2009;0.003). Genomic analysis identified 1007 somatic mutations, including in the BRAF, APC, RET, and ATM genes, with RET-NCOA4 fusions observed in the LM subgroup. CONCLUSION: LM is common in pPTC, and NMLNs&#x2009;>&#x2009;14 is a critical risk indicator. The genetic profile, particularly RET mutations, highlights potential therapeutic targets. Further large-scale studies are needed to validate these findings.

Humans↗
PubMed1998

Site-directed mutations in fungal laccase: effect on redox potential, activity and pH profile.

A Myceliophthora thermophila laccase and a Rhizoctonia solani laccase were mutated on a pentapeptide segment believed to be near the type-1 Cu site. The mutation L513F in Myceliophthora laccase and the mutation L470F in Rhizoctonia laccase took place at a position corresponding to the type-1 Cu axial methionine (M517) ligand in Zucchini ascorbate oxidase. The triple mutations V509L,S510E,G511A in Myceliophthora laccase and L466V,E467S,A468G in Rhizoctonia laccase involved a sequence segment whose homologue in ascorbate oxidase is flanked by the M517 and a type-1 Cu-ligating histidine (H512). The single mutation did not yield significant changes in the enzymic properties (including any significant increase in the redox potential of the type-1 Cu). In contrast, the triple mutation resulted in several significant changes. In comparison with the wild type, the Rhizoctonia and Myceliophthora laccase triple mutants had a phenol-oxidase activity whose pH optimum shifted 1 unit lower and higher, respectively. Although the redox potentials were not significantly altered, the Km, kcat and fluoride inhibition of the laccases were greatly changed by the mutations. The observed effects are interpreted as possible mutation-induced structural perturbations on the molecular recognition between the reducing substrate and laccase and on the electron transfer from the substrate to the type-1 Cu centre.

Amino Acid Sequence↗
PubMed1996

dCTP misincorporation in a Chinese hamster mutator phenotype: the role of GGA genetic context.

Clone CSA7 is a CHEF18 hamster cell line that shows an increased intracellular accumulation of dCTP. To localize the mutations that accumulate spontaneously in a functional gene of such a mutator phenotype, independent CSA7 mutants of the hypoxanthine-guanine phosphoribosyl transferase (hprt) gene were isolated and screened by a polymerase chain reaction-single strand conformation polymorphism technique. Sixty-two percent of mutants produced detectable changes of the strand migration profile and the mutations were preferentially localized in the exons 3 (31%) and 6 (62%). The sequencing of such exons revealed that the rate of C base incorporation was the major mutation pathway and that the A base of a GGA sequence was the preferential site of misincorporation.

Animals↗
PubMed2006

Modulating the proteinase inhibitory profile of a plant cystatin by single mutations at positively selected amino acid sites.

Cysteine proteinase inhibitors of the cystatin superfamily have several important functions in plants, including the inhibition of exogenous cysteine proteinases during herbivory or infection. Here we used a maximum-likelihood approach to assess whether plant cystatins, like other proteins implicated in host-pest interactions, have been subject to positive selection during the course of their evolution. Several amino acid sites were identified as being positively selected in cystatins from either Poaceae (monocots) and Solanaceae (dicots). These hypervariable sites were located at strategic positions on the protein: on each side of the conserved glycine residues in the N-terminal trunk, within the first and second inhibitory loops entering the active site of target enzymes, and surrounding the larfav motif, a sequence of unknown function conserved among plant cystatins. Supporting the assumption that positively selected, hypervariable sites are indicative of amino acid sites implicated in functional diversity, mutants of the 8th cystatin unit of tomato multicystatin including alternative residues at positively selected sites in the N-terminal trunk exhibited highly variable affinities for the cysteine proteases papain, cathepsin B and cathepsin H. Overall, these observations support the hypothesis that plant cystatins have been under selective pressure to evolve in response to predatory challenges by herbivorous enemies. They also indicate the potential of site-directed mutagenesis at positively selected sites for the generation of cystatins with improved binding properties.

Amino Acids↗
PubMed2026

Impact of Genomic Mutations on the Transcriptional Pathways and Tumor Microenvironment Landscape of Localized Early Prostate Cancer.

BACKGROUND: The management of intermediate-risk early prostate cancer (PCa) is challenging due to the difficulty in distinguishing indolent from aggressive tumors. This study explores the association between genomic alterations and the tumor and its microenvironment (TME) and implications for disease progression. METHODS: We performed multi-omic profiling in a cohort of 53 localized PCa using targeted sequencing, transcriptional, and proteomic spatial profiling. RESULTS: Somatic mutations and copy number alterations in RB1 (21%), PTEN (18%), and TP53 (9%) were identified. Kaplan-Meier analysis revealed that alterations in the RB and Cell Cycle pathways, particularly aberrations in PTEN, TP53, or RB1, were associated with shorter biochemical recurrence-free survival (p&#x2009;<&#x2009;0.001). Spatial proteomic analysis demonstrated a complex immune landscape in patients with mutations. The tumor compartment demonstrated higher expression of immune checkpoint markers, T-cell activation proteins, and proliferation markers; and a TME that is enriched with CD8&#x2009;+&#x2009;T cells and antigen-presenting cells, but also with immunosuppressive M2 macrophages, suggesting adaptive immune resistance. CONCLUSIONS: Our analysis demonstrates that genomic alterations in PTEN, TP53, or RB1 are not only prognostic for poor outcomes but are also associated with a unique, immunologically complex TME in this Brazilian cohort.

Humans↗
PubMed2001

pncA mutations in clinical Mycobacterium tuberculosis isolates from Korea.

BACKGROUND: Pyrazinamide (PZA) is among the first-line drugs for the treatment of tuberculosis. In vitro, it kills semidormant mycobacteria only at low pH. The purpose of this study was to compare PZA resistance with pyrazinamidase (PZase) activity and the genotype to better understand the molecular basis of PZA resistance and to expand the profile of pncA mutations worldwide. RESULTS: Of the 28 tested strains of Mycobacterium tuberculosis, 6 were susceptible to PZA and positive for PZase activity and had no pncA mutations. Twenty-one strains were resistant to PZA and negative for PZase activity and had mutations in the pncA gene, including 15 point mutations, 5 insertions, and 2 deletions. One strain had no mutation in the pncA gene, even though it was resistant to PZA and negative for PZase activity. Three isolates had adenine to guanine point mutations in the -11 upstream region, making this the most common type of pncA mutations in this study, with at least two different RFLP patterns. CONCLUSION: These data help in the understanding of the molecular basis of PZA resistance. An adenine to guanine point mutation in the -11 upstream region was the most common type of pncA mutation in our isolates. The results of pncA mutation analyses should be carefully interpreted for epidemiologic purposes.

Amidohydrolases↗
PubMed2003

Simultaneous detection of mutations associated with resistance to macrolides and quinolones in Campylobacter jejuni and C. coli using a PCR-line probe assay.

Quinolone and macrolide resistance of Campylobacter jejuni and Campylobacter coli mainly depend on a mutation in gyrA and in 23S rDNA, respectively. In order to detect quinolone and/or macrolide resistant C. jejuni and C. coli strains, a macrolide and quinolone line probe assay (MQ-LiPA) was developed and 42 C. jejuni and C. coli strains were tested to evaluate the efficiency of the assay. Profiles of the mutations in 23S rDNA and in gyrA characterized by MQ-LiPA agreed with resistance to macrolides and quinolones. MQ-LiPA is a rapid and simple method for simultaneous detection of quinolone and macrolide resistance of C. jejuni and C. coli. We could also discriminate between C. jejuni and C. coli using probes for detection of gyrA mutations in MQ-LiPA.

Campylobacter coli↗