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1.
Clin Genet ; 99(3): 425-429, 2021 03.
Article in English | MEDLINE | ID: mdl-33236357

ABSTRACT

mTOR dysregulation has been described in pathological conditions, such as cardiovascular and overgrowth disorders. Here we report on the first case of a patient with a complex congenital heart disease and an interstitial duplication in the short arm of chromosome 1, encompassing part of the mTOR gene. Our results suggest that an intragenic mTOR microduplication might play a role in the pathogenesis of non-syndromic congenital heart defects (CHDs) due to an upregulation of mTOR/Rictor and consequently an increased phosphorylation of PI3K/AKT and MEK/ERK signaling pathways in patient-derived amniocytes. This is the first report which shows a causative role of intragenic mTOR microduplication in the etiology of an isolated complex CHD.


Subject(s)
Genetic Predisposition to Disease , Heart Defects, Congenital/genetics , Heart Defects, Congenital/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Chromosomes, Human, Pair 1 , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Heart Defects, Congenital/diagnosis , Humans , Infant , Mitogen-Activated Protein Kinase Kinases/metabolism , Mutation , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Up-Regulation
2.
Nucleic Acids Res ; 46(11): 5587-5600, 2018 06 20.
Article in English | MEDLINE | ID: mdl-29733381

ABSTRACT

The HSF and FOXO families of transcription factors play evolutionarily conserved roles in stress resistance and lifespan. In humans, the rs2802292 G-allele at FOXO3 locus has been associated with longevity in all human populations tested; moreover, its copy number correlated with reduced frequency of age-related diseases in centenarians. At the molecular level, the intronic rs2802292 G-allele correlated with increased expression of FOXO3, suggesting that FOXO3 intron 2 may represent a regulatory region. Here we show that the 90-bp sequence around the intronic single nucleotide polymorphism rs2802292 has enhancer functions, and that the rs2802292 G-allele creates a novel HSE binding site for HSF1, which induces FOXO3 expression in response to diverse stress stimuli. At the molecular level, HSF1 mediates the occurrence of a promoter-enhancer interaction at FOXO3 locus involving the 5'UTR and the rs2802292 region. These data were confirmed in various cellular models including human HAP1 isogenic cell lines (G/T). Our functional studies highlighted the importance of the HSF1-FOXO3-SOD2/CAT/GADD45A cascade in cellular stress response and survival by promoting ROS detoxification, redox balance and DNA repair. Our findings suggest the existence of an HSF1-FOXO3 axis in human cells that could be involved in stress response pathways functionally regulating lifespan and disease susceptibility.


Subject(s)
Enhancer Elements, Genetic , Forkhead Box Protein O3/genetics , Heat Shock Transcription Factors/metabolism , Polymorphism, Single Nucleotide , Stress, Physiological/genetics , Transcriptional Activation , 5' Untranslated Regions , Alleles , Binding Sites , Cell Line , Cell Survival , Cells, Cultured , Forkhead Box Protein O3/biosynthesis , Humans , Introns , Longevity/genetics , Promoter Regions, Genetic
3.
PLoS One ; 10(4): e0123092, 2015.
Article in English | MEDLINE | ID: mdl-25915946

ABSTRACT

BACKGROUND: PIK3CA-related overgrowth spectrum (PROS) include a group of disorders that affect only the terminal portion of a limb, such as type I macrodactyly, and conditions like fibroadipose overgrowth (FAO), megalencephaly-capillary malformation (MCAP) syndrome, congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome and Hemihyperplasia Multiple Lipomatosis (HHML). Heterozygous postzygotic PIK3CA mutations are frequently identified in these syndromes, while timing and tissue specificity of the mutational event are likely responsible for the extreme phenotypic variability observed. METHODS: We carried out a combination of Sanger sequencing and targeted deep sequencing of genes involved in the PI3K/AKT/mTOR pathway in three patients (1 MCAP and 2 FAO) to identify causative mutations, and performed immunoblot analyses to assay the phosphorylation status of AKT and P70S6K in affected dermal fibroblasts. In addition, we evaluated their ability to grow in the absence of serum and their response to the PI3K inhibitors wortmannin and LY294002 in vitro. RESULTS AND CONCLUSION: Our data indicate that patients' cells showed constitutive activation of the PI3K/Akt pathway. Of note, PI3K pharmacological blockade resulted in a significant reduction of the proliferation rate in culture, suggesting that inhibition of PI3K might prove beneficial in future therapies for PROS patients.


Subject(s)
Congenital Abnormalities/genetics , Mutation , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Adipose Tissue/metabolism , Adipose Tissue/pathology , Cells, Cultured , Child , Class I Phosphatidylinositol 3-Kinases , Congenital Abnormalities/diagnosis , Connective Tissue/metabolism , Connective Tissue/pathology , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Infant , Male , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Zygote/metabolism
4.
Cancer Lett ; 353(1): 41-51, 2014 Oct 10.
Article in English | MEDLINE | ID: mdl-25038272

ABSTRACT

Bcl-6 translocation is a genetic alteration that is commonly detected in Primary Central Nervous System Lymphoma. The role of this protein in cerebral tumors is unclear. In this study we investigated Bcl-6 translocation and its transcriptional and translational levels in formalin-fixed, paraffin-embedded cerebral tissue sections from glioblastoma (GBM), low-grade glioma (Astrocytoma grade II and III), and meningioma patients, and correlated them with apoptotic processes and p53 and caspase-3 expression. The results showed a frequency of 36.6% of Bcl-6 translocation in GBM patients and a decreased expression in low-grade glioma patients, correlated with the severity of the disease. Bcl-6 translocation induced an overexpression of both Bcl-6 protein and messenger in GBM, inhibiting apoptotic processes and caspases 3 expression. On the contrary, in low-grade gliomas and meningiomas Bcl-6 expression was reduced, resulting in an increase of apoptotic processes. Finally, p53 expression levels in brain tumors were comparable to Bcl-6 levels. Overall, these data demonstrate, for the first time, that the Bcl-6 gene translocates in GBM patients and that its translocation and expression are correlated with apoptosis inhibition, indicating a key role for this gene in the control of cellular proliferation. This study offers further insights into glioblastoma biology, and supports Bcl-6 as a new diagnostic marker to evaluate the disease severity.


Subject(s)
Biomarkers, Tumor/genetics , DNA-Binding Proteins/genetics , Glioblastoma/genetics , Translocation, Genetic , Adult , Aged , Aged, 80 and over , Apoptosis , Biomarkers, Tumor/analysis , Brain Neoplasms/chemistry , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Caspase 3/analysis , Cell Proliferation , DNA-Binding Proteins/analysis , Female , Gene Expression Regulation, Neoplastic , Glioblastoma/chemistry , Glioblastoma/pathology , Humans , Male , Middle Aged , Neoplasm Grading , Proto-Oncogene Mas , Proto-Oncogene Proteins c-bcl-6 , RNA, Messenger/analysis , Retrospective Studies , Tumor Suppressor Protein p53/analysis
5.
J Occup Environ Med ; 51(7): 811-21, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19528831

ABSTRACT

OBJECTIVE: To evaluate the variation of some biomarkers related to the level of enzymatic activity dependent on the different polymorphisms. METHODS: We studied 27 butadiene-exposed workers and 37 controls using different biomarkers of the genotoxic effect. The genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism-polymerase chain reaction techniques; the subjects were assigned to a specific group based on the microsomal epoxide hydrolase (mEH) activity predicted by their genotype (low, intermediate, high). RESULTS: The studied biomarkers were not able to discriminate between exposed and control individuals, but sister chromatid exchange (SCE) and high frequency cells were influenced by smoking habits. Smokers having fast microsomal epoxide hydrolase activity showed higher SCE frequency (7.61) respect to those presenting intermediate (5.86) or slow (6.65) enzymatic activity. CONCLUSIONS: On the basis of these results, can we suppose the existence of an "intermediate genotype" advantage (at least for induction of SCE)?


Subject(s)
Butadienes/pharmacokinetics , Mutagens/pharmacokinetics , Occupational Exposure/adverse effects , Polymorphism, Genetic , Adult , Biomarkers , Butadienes/administration & dosage , Butadienes/metabolism , Butadienes/poisoning , Cytogenetic Analysis , Humans , Inactivation, Metabolic , Male , Middle Aged , Molecular Sequence Data , Mutagens/administration & dosage , Mutagens/metabolism , Mutagens/poisoning , Polymerase Chain Reaction , Sister Chromatid Exchange , Young Adult
6.
Twin Res Hum Genet ; 10(4): 655-7, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17708708

ABSTRACT

In a previously published article (Resta et al., 2006) on Robert's syndrome in prenatal diagnosis, a case of a 36-year-old woman and her 36-year-old, nonconsanguineous husband were presented. Our findings suggest the existence of nonsense mediated decay (NMD) variability which could account for the varying severity reported in carriers of identical mutations. Furthermore, fetal cells were used to evaluate the influence of premature centromere separation (PCS) on the sister chromatid exchange (SCE) and micronucleus (MN) frequency. Given the similar variation observed in the SCE frequencies, dependent on tissue/cell type (amniotic fluid sample, chorionic villus sampling) and duration of in vitro cultures (48 hours or 72 hours), the idea was that this new piece of information could be interesting. It seems that the SCE frequency increased proportionally to the cell cycle increasing (1 degrees < 2 degrees < 3 degrees ... n). Obviously, our observations are too scarce to draw conclusions, but further investigation could be useful to corroborate or dispute these results, considering that the two techniques, (MN and SCE), are simple to perform and do not require expensive laboratory equipment.


Subject(s)
Abnormalities, Multiple/diagnosis , Chromosome Aberrations , Prenatal Diagnosis , Sister Chromatid Exchange , Abnormalities, Multiple/genetics , Amniocentesis , Amniotic Fluid/cytology , Cells, Cultured , Chorionic Villi Sampling , Epithelial Cells , Female , Fetus/cytology , Humans , Male , Micronucleus Tests , Pregnancy , Syndrome
8.
Acta Neuropathol ; 112(1): 106-11, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16733653

ABSTRACT

The Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder caused by inactivating germline mutations in the serine-threonine kinase gene LKB1, is characterized by mucocutaneous pigmentation, multiple gastrointestinal hamartomatous polyps, and by an increased risk for developing tumors involving several different organs. To date, no brain tumors have been described in PJS patients. In this report, we describe a case of ganglioglioma in a 22-year-old PJS patient. Single-strand conformation polymorphism-Heteroduplex analysis evidenced an abnormal pattern in exon 6 of the LKB1 gene. Sequencing revealed a 821delTinsAC mutation creating a termination codon 29 nucleotides downstream (p.Asn274fsX11). RNA studies showed an out-of-frame LKB1 isoform derived from the wild type allele and generated by exon 4 skipping. Since the LKB1 gene is expressed in the fetal and adult brain, our data would suggest its likely involvement in the pathogenesis of a subset of gangliogliomas.


Subject(s)
Brain Neoplasms/etiology , Brain Neoplasms/pathology , Ganglioglioma/etiology , Ganglioglioma/pathology , Peutz-Jeghers Syndrome/complications , AMP-Activated Protein Kinase Kinases , Adult , Base Sequence , Brain Neoplasms/genetics , DNA Mutational Analysis , Female , Ganglioglioma/genetics , Gene Expression , Gene Expression Profiling , Humans , Magnetic Resonance Imaging , Molecular Sequence Data , Mutation , Peutz-Jeghers Syndrome/genetics , Polymorphism, Single-Stranded Conformational , Protein Serine-Threonine Kinases/genetics , Reverse Transcriptase Polymerase Chain Reaction
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