167 results on '"Ciccodicola, Alfredo"'
Search Results
152. PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation.
- Author
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Aprile M, Cataldi S, Ambrosio MR, D'Esposito V, Lim K, Dietrich A, Blüher M, Savage DB, Formisano P, Ciccodicola A, and Costa V
- Subjects
- 3T3-L1 Cells, Adipogenesis genetics, Adult, Animals, Exons genetics, HEK293 Cells, Humans, Ligands, Mice, Mice, Inbred C57BL, Middle Aged, Models, Biological, Obesity genetics, PPAR gamma chemistry, PPAR gamma metabolism, Protein Domains, Serine-Arginine Splicing Factors metabolism, Transcription, Genetic, Adipocytes cytology, Adipocytes metabolism, Cell Differentiation genetics, Genes, Dominant, PPAR gamma genetics, RNA Splicing genetics
- Abstract
Peroxisome-proliferator-activated receptor γ (PPARγ) regulates glucose and lipid homeostasis, insulin signaling, and adipocyte differentiation. Here, we report the skipping of exon 5 as a legitimate splicing event generating PPARγΔ5, a previously unidentified naturally occurring truncated isoform of PPARγ, which lacks the entire ligand-binding domain. PPARγΔ5 is endogenously expressed in human adipose tissue and, during adipocyte differentiation, lacks ligand-dependent transactivation ability and acts as a dominant-negative isoform reducing PPARγ activity. Ligand-mediated PPARγ activation induces exon 5 skipping in a negative feedback loop, suggesting alternative splicing as a mechanism regulating PPARγ activity. PPARγΔ5 overexpression modifies the PPARγ-induced transcriptional network, significantly impairing the differentiation ability of adipocyte precursor cells. Additionally, PPARγΔ5 expression in subcutaneous adipose tissue positively correlates with BMI in two independent cohorts of overweight or obese and type 2 diabetic patients. From a functional perspective, PPARγΔ5 mimics PPARG dominant-negative mutated receptors, possibly contributing to adipose tissue dysfunction. These findings open an unexplored scenario in PPARG regulation and PPARγ-related diseases., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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153. RBPMetaDB: a comprehensive annotation of mouse RNA-Seq datasets with perturbations of RNA-binding proteins.
- Author
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Li J, Deng SP, Vieira J, Thomas J, Costa V, Tseng CS, Ivankovic F, Ciccodicola A, and Yu P
- Subjects
- Animals, Internet, Mice, Protein Domains, PubMed, Publications, Statistics as Topic, User-Computer Interface, Databases, Genetic, Molecular Sequence Annotation, RNA-Binding Proteins metabolism, Sequence Analysis, RNA
- Abstract
RNA-binding proteins (RBPs) may play a critical role in gene regulation in various diseases or biological processes by controlling post-transcriptional events such as polyadenylation, splicing and mRNA stabilization via binding activities to RNA molecules. Owing to the importance of RBPs in gene regulation, a great number of studies have been conducted, resulting in a large amount of RNA-Seq datasets. However, these datasets usually do not have structured organization of metadata, which limits their potentially wide use. To bridge this gap, the metadata of a comprehensive set of publicly available mouse RNA-Seq datasets with perturbed RBPs were collected and integrated into a database called RBPMetaDB. This database contains 292 mouse RNA-Seq datasets for a comprehensive list of 187 RBPs. These RBPs account for only ∼10% of all known RBPs annotated in Gene Ontology, indicating that most are still unexplored using high-throughput sequencing. This negative information provides a great pool of candidate RBPs for biologists to conduct future experimental studies. In addition, we found that DNA-binding activities are significantly enriched among RBPs in RBPMetaDB, suggesting that prior studies of these DNA- and RNA-binding factors focus more on DNA-binding activities instead of RNA-binding activities. This result reveals the opportunity to efficiently reuse these data for investigation of the roles of their RNA-binding activities. A web application has also been implemented to enable easy access and wide use of RBPMetaDB. It is expected that RBPMetaDB will be a great resource for improving understanding of the biological roles of RBPs.Database URL: http://rbpmetadb.yubiolab.org.
- Published
- 2018
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154. Glucose impairs tamoxifen responsiveness modulating connective tissue growth factor in breast cancer cells.
- Author
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Ambrosio MR, D'Esposito V, Costa V, Liguoro D, Collina F, Cantile M, Prevete N, Passaro C, Mosca G, De Laurentiis M, Di Bonito M, Botti G, Franco R, Beguinot F, Ciccodicola A, and Formisano P
- Abstract
Type 2 diabetes and obesity are negative prognostic factors in patients with breast cancer (BC). We found that sensitivity to tamoxifen was reduced by 2-fold by 25 mM glucose (High Glucose; HG) compared to 5.5 mM glucose (Low Glucose; LG) in MCF7 BC cells. Shifting from HG to LG ameliorated MCF7 cell responsiveness to tamoxifen. RNA-Sequencing of MCF7 BC cells revealed that cell cycle-related genes were mainly affected by glucose. Connective Tissue Growth Factor (CTGF) was identified as a glucose-induced modulator of cell sensitivity to tamoxifen. Co-culturing MCF7 cells with human adipocytes exposed to HG, enhanced CTGF mRNA levels and reduced tamoxifen responsiveness of BC cells. Inhibition of adipocyte-released IL8 reverted these effects. Interestingly, CTGF immuno-detection in bioptic specimens from women with estrogen receptor positive (ER
+ ) BC correlated with hormone therapy resistance, distant metastases, reduced overall and disease-free survival. Thus, glucose affects tamoxifen responsiveness directly modulating CTGF in BC cells, and indirectly promoting IL8 release by adipocytes., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.- Published
- 2017
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155. SFMetaDB: a comprehensive annotation of mouse RNA splicing factor RNA-Seq datasets.
- Author
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Li J, Tseng CS, Federico A, Ivankovic F, Huang YS, Ciccodicola A, Swanson MS, and Yu P
- Subjects
- Animals, Mice, Databases, Genetic, RNA Splicing genetics, RNA Splicing Factors genetics
- Abstract
Although the number of RNA-Seq datasets deposited publicly has increased over the past few years, incomplete annotation of the associated metadata limits their potential use. Because of the importance of RNA splicing in diseases and biological processes, we constructed a database called SFMetaDB by curating datasets related with RNA splicing factors. Our effort focused on the RNA-Seq datasets in which splicing factors were knocked-down, knocked-out or over-expressed, leading to 75 datasets corresponding to 56 splicing factors. These datasets can be used in differential alternative splicing analysis for the identification of the potential targets of these splicing factors and other functional studies. Surprisingly, only ∼15% of all the splicing factors have been studied by loss- or gain-of-function experiments using RNA-Seq. In particular, splicing factors with domains from a few dominant Pfam domain families have not been studied. This suggests a significant gap that needs to be addressed to fully elucidate the splicing regulatory landscape. Indeed, there are already mouse models available for ∼20 of the unstudied splicing factors, and it can be a fruitful research direction to study these splicing factors in vitro and in vivo using RNA-Seq. Database URL:http://sfmetadb.ece.tamu.edu/, (© The Author(s) 2017. Published by Oxford University Press.)
- Published
- 2017
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156. New somatic mutations and WNK1-B4GALNT3 gene fusion in papillary thyroid carcinoma.
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Costa V, Esposito R, Ziviello C, Sepe R, Bim LV, Cacciola NA, Decaussin-Petrucci M, Pallante P, Fusco A, and Ciccodicola A
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- Carcinoma enzymology, Carcinoma pathology, Carcinoma, Papillary, Case-Control Studies, DNA Helicases genetics, DNA Mutational Analysis, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Minor Histocompatibility Antigens, Neoplasm Staging, Nuclear Proteins genetics, Phenotype, Predictive Value of Tests, Proto-Oncogene Proteins c-cbl genetics, Receptor, Notch1 genetics, Reproducibility of Results, Thyroid Cancer, Papillary, Thyroid Neoplasms enzymology, Thyroid Neoplasms pathology, Transcription Factors genetics, Vacuolar Sorting Protein VPS15 genetics, WNK Lysine-Deficient Protein Kinase 1, Biomarkers, Tumor genetics, Carcinoma genetics, Gene Fusion, Intracellular Signaling Peptides and Proteins genetics, Mutation, Missense, N-Acetylgalactosaminyltransferases genetics, Protein Serine-Threonine Kinases genetics, Thyroid Neoplasms genetics
- Abstract
Papillary thyroid carcinoma (PTC) is the most frequent thyroid malignant neoplasia. Oncogene activation occurs in more than 70% of the cases. Indeed, about 40% of PTCs harbor mutations in BRAF gene, whereas RET rearrangements (RET/PTC oncogenes) are present in about 20% of cases. Finally, RAS mutations and TRK rearrangements account for about 5% each of these malignancies. We used RNA-Sequencing to identify fusion transcripts and mutations in cancer driver genes in a cohort of 18 PTC patients. Furthermore, we used targeted DNA sequencing to validate identified mutations. We extended the screening to 50 PTC patients and 30 healthy individuals. Using this approach we identified new missense mutations in CBL, NOTCH1, PIK3R4 and SMARCA4 genes. We found somatic mutations in DICER1, MET and VHL genes, previously found mutated in other tumors, but not described in PTC. We identified a new chimeric transcript generated by the fusion of WNK1 and B4GALNT3 genes, correlated with B4GALNT3 overexpression. Our data confirmed PTC genetic heterogeneity, revealing that gene expression correlates more with the mutation pattern than with tumor staging. Overall, this study provides new data about mutational landscape of this neoplasia, suggesting potential pharmacological adjuvant therapies against Notch signaling and chromatin remodeling enzymes.
- Published
- 2015
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157. Antigen delivery by filamentous bacteriophage fd displaying an anti-DEC-205 single-chain variable fragment confers adjuvanticity by triggering a TLR9-mediated immune response.
- Author
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Sartorius R, D'Apice L, Trovato M, Cuccaro F, Costa V, De Leo MG, Marzullo VM, Biondo C, D'Auria S, De Matteis MA, Ciccodicola A, and De Berardinis P
- Subjects
- Animals, Antigens metabolism, Antigens, CD immunology, CD8-Positive T-Lymphocytes immunology, Cell Surface Display Techniques, Cells, Cultured, Drug Carriers, Gene Expression Profiling, Immunity, Innate, Lectins, C-Type immunology, Mice, Inbred C57BL, Minor Histocompatibility Antigens, Receptors, Cell Surface immunology, Single-Chain Antibodies immunology, Adjuvants, Immunologic metabolism, Antigens immunology, Antigens, CD metabolism, Dendritic Cells immunology, Inovirus genetics, Lectins, C-Type metabolism, Receptors, Cell Surface metabolism, Single-Chain Antibodies metabolism, Toll-Like Receptor 9 metabolism
- Abstract
Filamentous bacteriophage fd particles delivering antigenic determinants via DEC-205 (fdsc-αDEC) represent a powerful delivery system that induces CD8(+) T-cell responses even when administered in the absence of adjuvants or maturation stimuli for dendritic cells. In order to investigate the mechanisms of this activity, RNA-Sequencing of fd-pulsed dendritic cells was performed. A significant differential expression of genes involved in innate immunity, co-stimulation and cytokine production was observed. In agreement with these findings, we demonstrate that induction of proinflammatory cytokines and type I interferon by fdsc-αDEC was MYD88 mediated and TLR9 dependent. We also found that fdsc-αDEC is delivered into LAMP-1-positive compartments and co-localizes with TLR9. Thus, phage particles containing a single-strand DNA genome rich in CpG motifs delivered via DEC-205 are able to intercept and trigger the active TLR9 innate immune receptor into late endosome/lysosomes and to enhance the immunogenicity of the displayed antigenic determinants. These findings make fd bacteriophage a valuable tool for immunization without administering exogenous adjuvants., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2015
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158. Is PPARG the key gene in diabetic retinopathy?
- Author
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Costa V and Ciccodicola A
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- Humans, Biological Products therapeutic use, Diabetic Retinopathy genetics, Diabetic Retinopathy physiopathology, PPAR gamma genetics, PPAR gamma metabolism
- Abstract
Diabetic retinopathy, a microvascular complication of diabetes mellitus, is major cause of non-inherited blindness among adults. Although diabetic retinopathy is a common complication of diabetes, we still know little about the underlying molecular mechanisms. In recent years, complex connections between important molecules and pathways in the onset and progression of diabetic retinopathy, such as advanced glycation end products, oxidative stress and inflammation, have been elucidated. Biochemical, genetic and functional studies strongly indicate peroxisome proliferator-activated receptor-γ (PPARγ), a pleiotropic transcription factor, as a primary target in the treatment of diabetic retinopathy. In this issue, Song et al. detail the role of PPARγ in diabetic retinopathy-related disorders, illustrating PPARγ-mediated inhibition of diabetes-induced leukostasis and leakage, and its beneficial role in modulating inflammation, angiogenesis and apoptosis in retinal and endothelial cells. Moreover, they describe alternative treatments for diabetic retinopathy, such as plant-derived PPARγ ligands, proposing their use - in combination with standard therapies - for modulation of diabetic retinopathy., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)
- Published
- 2012
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159. Impairment of circulating endothelial progenitors in Down syndrome.
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Costa V, Sommese L, Casamassimi A, Colicchio R, Angelini C, Marchesano V, Milone L, Farzati B, Giovane A, Fiorito C, Rienzo M, Picardi M, Avallone B, Marco Corsi M, Sarubbi B, Calabrò R, Salvatore P, Ciccodicola A, and Napoli C
- Subjects
- Cat-Scratch Disease genetics, Chemokine CXCL12 blood, Chemokine CXCL12 genetics, Chromosomes, Human, Pair 21, Down Syndrome genetics, Down Syndrome metabolism, Humans, Hydrogen Peroxide metabolism, Oxidative Stress, Phenotype, Stem Cells metabolism, Trisomy, Down Syndrome pathology, Endothelium, Vascular cytology, Stem Cells pathology
- Abstract
Background: Pathological angiogenesis represents a critical issue in the progression of many diseases. Down syndrome is postulated to be a systemic anti-angiogenesis disease model, possibly due to increased expression of anti-angiogenic regulators on chromosome 21. The aim of our study was to elucidate some features of circulating endothelial progenitor cells in the context of this syndrome., Methods: Circulating endothelial progenitors of Down syndrome affected individuals were isolated, in vitro cultured and analyzed by confocal and transmission electron microscopy. ELISA was performed to measure SDF-1α plasma levels in Down syndrome and euploid individuals. Moreover, qRT-PCR was used to quantify expression levels of CXCL12 gene and of its receptor in progenitor cells. The functional impairment of Down progenitors was evaluated through their susceptibility to hydroperoxide-induced oxidative stress with BODIPY assay and the major vulnerability to the infection with human pathogens. The differential expression of crucial genes in Down progenitor cells was evaluated by microarray analysis., Results: We detected a marked decrease of progenitors' number in young Down individuals compared to euploid, cell size increase and some major detrimental morphological changes. Moreover, Down syndrome patients also exhibited decreased SDF-1α plasma levels and their progenitors had a reduced expression of SDF-1α encoding gene and of its membrane receptor. We further demonstrated that their progenitor cells are more susceptible to hydroperoxide-induced oxidative stress and infection with Bartonella henselae. Further, we observed that most of the differentially expressed genes belong to angiogenesis, immune response and inflammation pathways, and that infected progenitors with trisomy 21 have a more pronounced perturbation of immune response genes than infected euploid cells., Conclusions: Our data provide evidences for a reduced number and altered morphology of endothelial progenitor cells in Down syndrome, also showing the higher susceptibility to oxidative stress and to pathogen infection compared to euploid cells, thereby confirming the angiogenesis and immune response deficit observed in Down syndrome individuals.
- Published
- 2010
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160. Nutritional genomics era: opportunities toward a genome-tailored nutritional regimen.
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Costa V, Casamassimi A, and Ciccodicola A
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- DNA Methylation, Food, Gene Expression Regulation, Genetic Testing, Haplotypes, Health Promotion legislation & jurisprudence, Humans, Polymorphism, Single Nucleotide, Precision Medicine, Diet, Genomics, Nutritional Sciences
- Abstract
There is increasing evidence indicating that nutritional genomics represents a promise to improve public health. This goal will be reached by highlighting the mechanisms through which diet can reduce the risk of monogenic and common polygenic diseases. Indeed, nutrition is a very relevant environmental factor involved in the development and progression of metabolic disorders, as well as other kind of diseases. The revolutionary changes in the field of genomics have led to the development and implementation of new technologies and molecular tools. These technologies have a useful application in the nutritional sciences, since they allow a more precise and accurate analysis of biochemical alterations, in addition to filling fundamental gaps in the knowledge of nutrient-genome interactions in both health and disease. Overall, these advances will open undiscovered ways in genome-customized diets for disease prevention and therapy. This review summarizes the recent knowledge concerning this novel nutritional approach, paying attention to the human genome variations, such as single-nucleotide polymorphisms and copy number variations, gene expression and innovative molecular tools to reveal them., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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161. New evidence for the correlation of the p.G130V mutation in the GJB2 gene and syndromic hearing loss with palmoplantar keratoderma.
- Author
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Iossa S, Chinetti V, Auletta G, Laria C, De Luca M, Rienzo M, Giannini P, Delfino M, Ciccodicola A, Marciano E, and Franzé A
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- Audiometry, Pure-Tone, Child, Preschool, Connexin 26, Female, Genes, Dominant, Genotype, Hearing Loss, Sensorineural physiopathology, Humans, Keratoderma, Palmoplantar pathology, Male, Pedigree, Phenotype, Syndrome, Connexins genetics, Hearing Loss, Sensorineural complications, Hearing Loss, Sensorineural genetics, Keratoderma, Palmoplantar complications, Keratoderma, Palmoplantar genetics, Point Mutation
- Abstract
The GJB2 gene located on chromosome 13q12 and encoding the connexin 26 (Cx26) protein, a transmembrane protein involved in cell-cell attachment of almost all tissues, including the skin, causes autosomal recessive and sometimes dominant nonsyndromic sensorineural hearing loss. GJB2 mutations have also been identified in syndromic disorders exhibiting hearing loss associated with skin problems. Recently, a new mutation, p.G130V in the GJB2 gene has been reported as causative for Vohwinkel syndrome. In this case the p.G130V mutation was found in two patients (son and father) with palmoplantar keratoderma. The father also showed also skin constrictions of the 2nd and 3rd toes of the right foot. Here, we report on another family with palmoplantar keratoderma associated with a dominant form of hearing loss confirming the genotype-phenotype correlation between the mutation p.G130V and the skin abnormalities observed in syndromic disorders with hearing loss as described by [Snoeckx et al. (2005) Hum Mutat 26:60-65].
- Published
- 2009
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162. Detrimental effects of Bartonella henselae are counteracted by L-arginine and nitric oxide in human endothelial progenitor cells.
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Salvatore P, Casamassimi A, Sommese L, Fiorito C, Ciccodicola A, Rossiello R, Avallone B, Grimaldi V, Costa V, Rienzo M, Colicchio R, Williams-Ignarro S, Pagliarulo C, Prudente ME, Abbondanza C, Lamberti F, Baroni A, Buommino E, Farzati B, Tufano MA, Ignarro LJ, and Napoli C
- Subjects
- Bacterial Adhesion drug effects, Bartonella henselae cytology, Bartonella henselae ultrastructure, Cell Count, Cell Survival drug effects, Endothelial Cells cytology, Endothelial Cells enzymology, Endothelial Cells ultrastructure, Enzyme Activation drug effects, Flow Cytometry, Gene Expression Regulation drug effects, Humans, Stem Cells cytology, Stem Cells enzymology, Stem Cells ultrastructure, Tumor Necrosis Factor-alpha pharmacology, p38 Mitogen-Activated Protein Kinases metabolism, Arginine pharmacology, Bartonella henselae drug effects, Endothelial Cells microbiology, Nitric Oxide pharmacology, Stem Cells microbiology
- Abstract
The recruitment of circulating endothelial progenitor cells (EPCs) might have a beneficial effect on the clinical course of several diseases. Endothelial damage and detachment of endothelial cells are known to occur in infection, tissue ischemia, and sepsis. These detrimental effects in EPCs are unknown. Here we elucidated whether human EPCs internalize Bartonella henselae constituting a circulating niche of the pathogen. B. henselae invades EPCs as shown by gentamicin protection assays and transmission electron microscopy (TEM). Dil-Ac-LDL/lectin double immunostaining and fluorescence-activated cell sorting (FACS) analysis of EPCs revealed EPC bioactivity after infection with B. henselae. Nitric oxide (NO) and its precursor l-arginine (l-arg) exert a plethora of beneficial effects on vascular function and modulation of immune response. Therefore, we tested also the hypothesis that l-arg (1-30 mM) would affect the infection of B. henselae or tumor necrosis factor (TNF) in EPCs. Our data provide evidence that l-arg counteracts detrimental effects induced by TNF or Bartonella infections via NO (confirmed by DETA-NO and L-NMMA experiments) and by modulation of p38 kinase phosphorylation. Microarray analysis indicated several genes involved in immune response were differentially expressed in Bartonella-infected EPCs, whereas these genes returned in steady state when cells were exposed to sustained doses of l-arg. This mechanism may have broad therapeutic applications in tissue ischemia, angiogenesis, immune response, and sepsis.
- Published
- 2008
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163. Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement.
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Gargiulo A, Auricchio R, Barone MV, Cotugno G, Reardon W, Milla PJ, Ballabio A, Ciccodicola A, and Auricchio A
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- Actins physiology, Amino Acid Sequence, Base Sequence, Blotting, Western, Cells, Cultured, Filamins, Genes, Recessive, Humans, Male, Microscopy, Fluorescence, Molecular Sequence Data, Pedigree, Protein Biosynthesis genetics, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Central Nervous System Diseases genetics, Contractile Proteins genetics, Frameshift Mutation genetics, Genetic Diseases, X-Linked genetics, Genetic Predisposition to Disease, Intestinal Pseudo-Obstruction genetics, Microfilament Proteins genetics
- Abstract
We have previously reported that an X-linked recessive form of chronic idiopathic intestinal pseudo-obstruction (CIIPX) maps to Xq28. To select candidate genes for the disease, we analyzed the expression in murine fetal brain and intestine of 56 genes from the critical region. We selected and sequenced seven genes and found that one affected male from a large CIIPX-affected kindred bears a 2-bp deletion in exon 2 of the FLNA gene that is present at the heterozygous state in the carrier females of the family. The frameshift mutation is located between two close methionines at the filamin N terminus and is predicted to produce a protein truncated shortly after the first predicted methionine. Loss-of-function FLNA mutations have been associated with X-linked dominant nodular ventricular heterotopia (PVNH), a central nervous system (CNS) migration defect that presents with seizures in females and lethality in males. Notably, the affected male bearing the FLNA deletion had signs of CNS involvement and potentially has PVNH. To understand how the severe frameshift mutation we found can explain the CIIPX phenotype and its X-linked recessive inheritance, we transiently expressed both the wild- type and mutant filamin in cell culture and found that filamin translation can start from either of the two initial methionines in these conditions. Therefore, translation of a normal shorter filamin can occur in vitro from the second methionine downstream of the 2-bp insertion we found. We confirmed this, demonstrating that the filamin protein is present in the patient's lymphoblastoid cell line that shows abnormal cytoskeletal actin organization compared with normal lymphoblasts. We conclude that the filamin N terminal region between the initial two methionines is crucial for proper enteric neuron development.
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- 2007
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164. Identification of a novel mutation in the myosin VIIA motor domain in a family with autosomal dominant hearing loss (DFNA11).
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Di Leva F, D'Adamo P, Cubellis MV, D'Eustacchio A, Errichiello M, Saulino C, Auletta G, Giannini P, Donaudy F, Ciccodicola A, Gasparini P, Franzè A, and Marciano E
- Subjects
- Amino Acid Sequence, Auditory Threshold, Base Sequence, Chromosome Mapping, Dyneins chemistry, Female, Genotype, Humans, Male, Models, Molecular, Molecular Sequence Data, Myosin VIIa, Myosins chemistry, Pedigree, Vestibular Diseases complications, Vestibular Diseases genetics, Chromosome Disorders genetics, Dyneins genetics, Hearing Loss, Sensorineural genetics, Mutation, Missense genetics, Myosins genetics
- Abstract
We ascertained a large Italian family with an autosomal dominant form of non-syndromic sensorineural hearing loss with vestibular involvement. A genome-wide scan found linkage to locus DFNA11. Sequencing of the MYO7A gene in the linked region identified a new missense mutation resulting in an Ala230Val change in the motor domain of the myosin VIIA. Myosin VIIA has already been implicated in several forms of deafness, but this is the third mutation causing a dominant form of deafness, located in the myosin VIIA motor domain in a region never involved in hearing loss until now. A modelled protein structure of myosin VII motor domain provides evidence for a significant functional effect of this missense mutation., (Copyright (c) 2006 S. Karger AG, Basel.)
- Published
- 2006
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165. Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach.
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Tosi GM, Trimarchi C, Macaluso M, La Sala D, Ciccodicola A, Lazzi S, Massaro-Giordano M, Caporossi A, Giordano A, and Cinti C
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- Azacitidine analogs & derivatives, Azacitidine pharmacology, Base Sequence, Blotting, Western, Cell Line, Tumor, Cell Proliferation drug effects, DNA Methylation drug effects, DNA Mutational Analysis, DNA Primers, Decitabine, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Molecular Sequence Data, Retinoblastoma-Like Protein p130, Epigenesis, Genetic, Genes, Tumor Suppressor, Proteins genetics, Retinal Neoplasms genetics, Retinoblastoma genetics
- Abstract
Human retinoblastoma occurs in two forms (familial and sporadic) both due to biallelic mutation of the RB1/p105 gene even if its loss is insufficient for malignancy. We have recently reported that loss of expression of the retinoblastoma-related protein pRb2/p130 correlates with low apoptotic index, suggesting that RB2/p130 gene could be involved in retinoblastoma. Mutational analysis of RB2/p130 in primary tumors showed a tight correlation between Exon 1 mutations and pRb2/p130 expression level in sporadic retinoblastoma. These mutations are located within a CpG-enriched region prone to de novo methylation. Analysis of RB2/p130 methylation status revealed that epigenetic events, most probably consequent to the Exon 1 mutations, determined the observed phenotype. Treatment of Weri-Rb1 cell line by 5-Aza-dC induced an increase in expression level of pRb2/p130, E2F1, p73 and p53. Overall, our results highlight a crucial role of epigenetic events in sporadic retinoblastoma, which opens a perspective for new therapeutic approaches.
- Published
- 2005
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166. A novel peroxisome proliferator-activated receptor gamma isoform with dominant negative activity generated by alternative splicing.
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Sabatino L, Casamassimi A, Peluso G, Barone MV, Capaccio D, Migliore C, Bonelli P, Pedicini A, Febbraro A, Ciccodicola A, and Colantuoni V
- Subjects
- Animals, Blotting, Western, Bromodeoxyuridine pharmacology, COS Cells, Caco-2 Cells, Cell Nucleus metabolism, Cell Proliferation, Chromans pharmacology, Colorectal Neoplasms metabolism, DNA, Complementary metabolism, Exons, Genes, Dominant, Genes, Reporter, Genetic Vectors, Humans, In Vitro Techniques, Introns, Ligands, Luciferases metabolism, Mice, Microscopy, Fluorescence, Models, Genetic, NIH 3T3 Cells, Open Reading Frames, PPAR gamma genetics, Protein Biosynthesis, Protein Isoforms, Protein Structure, Tertiary, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Thiazolidinediones pharmacology, Transcriptional Activation, Transfection, Troglitazone, Alternative Splicing, PPAR gamma chemistry, PPAR gamma metabolism
- Abstract
We examined the peroxisome proliferator-activated receptor gamma (PPARG) locus in an attempt to identify expressed sequence tags and/or conserved non-coding sequences in the intron sequences containing open reading frames and potentially able to encode new proteins. We identified a new PPARG transcript, defined gammaORF4, which harbors a readthrough in intron 4. The expected translated protein lacks the ligand-binding domain encoded by exons 5 and 6. We identified the transcript in human tumor cell lines and tissues, synthesized the cDNA, and cloned it in expression vectors. Using transient transfections, we found that gammaORF4 cDNA is translated into a predominantly nuclear protein that does not transactivate a reporter gene. Moreover, the isoform is dominant negative versus PPARgamma. Interestingly, gammaORF4 was expressed in vivo in a series of sporadic colorectal cancers. In some cases, it was expressed, albeit at lower levels, also in the mucosa adjacent to the tumors, suggesting that it may be related to tumorigenesis. A tumorigenic effect of gammaORF4 is in line with our finding that gammaORF4 has not only lost the capacity to restrain cell growth but has acquired the potential to stimulate it. In conclusion, this study demonstrates that gammaORF4 is expressed in vivo, that it has lost some PPARgamma properties, and that it affects PPARgamma functioning. The ability to counteract PPARgamma suggests that gammaORF4 plays a role in the pathogenesis of colorectal cancers.
- Published
- 2005
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167. The DNA sequence of the human X chromosome.
- Author
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Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, Platzer M, Howell GR, Burrows C, Bird CP, Frankish A, Lovell FL, Howe KL, Ashurst JL, Fulton RS, Sudbrak R, Wen G, Jones MC, Hurles ME, Andrews TD, Scott CE, Searle S, Ramser J, Whittaker A, Deadman R, Carter NP, Hunt SE, Chen R, Cree A, Gunaratne P, Havlak P, Hodgson A, Metzker ML, Richards S, Scott G, Steffen D, Sodergren E, Wheeler DA, Worley KC, Ainscough R, Ambrose KD, Ansari-Lari MA, Aradhya S, Ashwell RI, Babbage AK, Bagguley CL, Ballabio A, Banerjee R, Barker GE, Barlow KF, Barrett IP, Bates KN, Beare DM, Beasley H, Beasley O, Beck A, Bethel G, Blechschmidt K, Brady N, Bray-Allen S, Bridgeman AM, Brown AJ, Brown MJ, Bonnin D, Bruford EA, Buhay C, Burch P, Burford D, Burgess J, Burrill W, Burton J, Bye JM, Carder C, Carrel L, Chako J, Chapman JC, Chavez D, Chen E, Chen G, Chen Y, Chen Z, Chinault C, Ciccodicola A, Clark SY, Clarke G, Clee CM, Clegg S, Clerc-Blankenburg K, Clifford K, Cobley V, Cole CG, Conquer JS, Corby N, Connor RE, David R, Davies J, Davis C, Davis J, Delgado O, Deshazo D, Dhami P, Ding Y, Dinh H, Dodsworth S, Draper H, Dugan-Rocha S, Dunham A, Dunn M, Durbin KJ, Dutta I, Eades T, Ellwood M, Emery-Cohen A, Errington H, Evans KL, Faulkner L, Francis F, Frankland J, Fraser AE, Galgoczy P, Gilbert J, Gill R, Glöckner G, Gregory SG, Gribble S, Griffiths C, Grocock R, Gu Y, Gwilliam R, Hamilton C, Hart EA, Hawes A, Heath PD, Heitmann K, Hennig S, Hernandez J, Hinzmann B, Ho S, Hoffs M, Howden PJ, Huckle EJ, Hume J, Hunt PJ, Hunt AR, Isherwood J, Jacob L, Johnson D, Jones S, de Jong PJ, Joseph SS, Keenan S, Kelly S, Kershaw JK, Khan Z, Kioschis P, Klages S, Knights AJ, Kosiura A, Kovar-Smith C, Laird GK, Langford C, Lawlor S, Leversha M, Lewis L, Liu W, Lloyd C, Lloyd DM, Loulseged H, Loveland JE, Lovell JD, Lozado R, Lu J, Lyne R, Ma J, Maheshwari M, Matthews LH, McDowall J, McLaren S, McMurray A, Meidl P, Meitinger T, Milne S, Miner G, Mistry SL, Morgan M, Morris S, Müller I, Mullikin JC, Nguyen N, Nordsiek G, Nyakatura G, O'Dell CN, Okwuonu G, Palmer S, Pandian R, Parker D, Parrish J, Pasternak S, Patel D, Pearce AV, Pearson DM, Pelan SE, Perez L, Porter KM, Ramsey Y, Reichwald K, Rhodes S, Ridler KA, Schlessinger D, Schueler MG, Sehra HK, Shaw-Smith C, Shen H, Sheridan EM, Shownkeen R, Skuce CD, Smith ML, Sotheran EC, Steingruber HE, Steward CA, Storey R, Swann RM, Swarbreck D, Tabor PE, Taudien S, Taylor T, Teague B, Thomas K, Thorpe A, Timms K, Tracey A, Trevanion S, Tromans AC, d'Urso M, Verduzco D, Villasana D, Waldron L, Wall M, Wang Q, Warren J, Warry GL, Wei X, West A, Whitehead SL, Whiteley MN, Wilkinson JE, Willey DL, Williams G, Williams L, Williamson A, Williamson H, Wilming L, Woodmansey RL, Wray PW, Yen J, Zhang J, Zhou J, Zoghbi H, Zorilla S, Buck D, Reinhardt R, Poustka A, Rosenthal A, Lehrach H, Meindl A, Minx PJ, Hillier LW, Willard HF, Wilson RK, Waterston RH, Rice CM, Vaudin M, Coulson A, Nelson DL, Weinstock G, Sulston JE, Durbin R, Hubbard T, Gibbs RA, Beck S, Rogers J, and Bentley DR
- Subjects
- Animals, Antigens, Neoplasm genetics, Centromere genetics, Chromosomes, Human, Y genetics, Contig Mapping, Crossing Over, Genetic genetics, Dosage Compensation, Genetic, Female, Genetic Linkage genetics, Genetics, Medical, Humans, Male, Polymorphism, Single Nucleotide genetics, RNA genetics, Repetitive Sequences, Nucleic Acid genetics, Sequence Homology, Nucleic Acid, Testis metabolism, Chromosomes, Human, X genetics, Evolution, Molecular, Genomics, Sequence Analysis, DNA
- Abstract
The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.
- Published
- 2005
- Full Text
- View/download PDF
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