111 results on '"Binda, Anna"'
Search Results
2. HCN ion channels and accessory proteins in epilepsy: genetic analysis of a large cohort of patients and review of the literature
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DiFrancesco, Jacopo C., Castellotti, Barbara, Milanesi, Raffaella, Ragona, Francesca, Freri, Elena, Canafoglia, Laura, Franceschetti, Silvana, Ferrarese, Carlo, Magri, Stefania, Taroni, Franco, Costa, Cinzia, Labate, Angelo, Gambardella, Antonio, Solazzi, Roberta, Binda, Anna, Rivolta, Ilaria, Di Gennaro, Giancarlo, Casciato, Sara, D’Incerti, Ludovico, Barbuti, Andrea, DiFrancesco, Dario, Granata, Tiziana, and Gellera, Cinzia
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- 2019
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3. Unravelling Novel SCN5A Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights
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Frosio, Anthony, primary, Micaglio, Emanuele, additional, Polsinelli, Ivan, additional, Calamaio, Serena, additional, Melgari, Dario, additional, Prevostini, Rachele, additional, Ghiroldi, Andrea, additional, Binda, Anna, additional, Carrera, Paola, additional, Villa, Marco, additional, Mastrocinque, Flavio, additional, Presi, Silvia, additional, Salerno, Raffaele, additional, Boccellino, Antonio, additional, Anastasia, Luigi, additional, Ciconte, Giuseppe, additional, Ricagno, Stefano, additional, Pappone, Carlo, additional, and Rivolta, Ilaria, additional
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- 2023
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4. A novel de novo HCN2 loss‐of‐function variant causing developmental and epileptic encephalopathy treated with a ketogenic diet
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DiFrancesco, Jacopo C., primary, Ragona, Francesca, additional, Murano, Carmen, additional, Frosio, Anthony, additional, Melgari, Dario, additional, Binda, Anna, additional, Calamaio, Serena, additional, Prevostini, Rachele, additional, Mauri, Mario, additional, Canafoglia, Laura, additional, Castellotti, Barbara, additional, Messina, Giuliana, additional, Gellera, Cinzia, additional, Previtali, Roberto, additional, Veggiotti, Pierangelo, additional, Milanesi, Raffaella, additional, Barbuti, Andrea, additional, Solazzi, Roberta, additional, Freri, Elena, additional, Granata, Tiziana, additional, and Rivolta, Ilaria, additional
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- 2023
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- View/download PDF
5. A novel de novo HCN2 loss-of-function variant causing developmental and epileptic encephalopathy treated with a ketogenic diet
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Difrancesco, J, Ragona, F, Murano, C, Frosio, A, Melgari, D, Binda, A, Calamaio, S, Prevostini, R, Mauri, M, Canafoglia, L, Castellotti, B, Messina, G, Gellera, C, Previtali, R, Veggiotti, P, Milanesi, R, Barbuti, A, Solazzi, R, Freri, E, Granata, T, Rivolta, I, DiFrancesco, Jacopo C, Ragona, Francesca, Murano, Carmen, Frosio, Anthony, Melgari, Dario, Binda, Anna, Calamaio, Serena, Prevostini, Rachele, Mauri, Mario, Canafoglia, Laura, Castellotti, Barbara, Messina, Giuliana, Gellera, Cinzia, Previtali, Roberto, Veggiotti, Pierangelo, Milanesi, Raffaella, Barbuti, Andrea, Solazzi, Roberta, Freri, Elena, Granata, Tiziana, Rivolta, Ilaria, Difrancesco, J, Ragona, F, Murano, C, Frosio, A, Melgari, D, Binda, A, Calamaio, S, Prevostini, R, Mauri, M, Canafoglia, L, Castellotti, B, Messina, G, Gellera, C, Previtali, R, Veggiotti, P, Milanesi, R, Barbuti, A, Solazzi, R, Freri, E, Granata, T, Rivolta, I, DiFrancesco, Jacopo C, Ragona, Francesca, Murano, Carmen, Frosio, Anthony, Melgari, Dario, Binda, Anna, Calamaio, Serena, Prevostini, Rachele, Mauri, Mario, Canafoglia, Laura, Castellotti, Barbara, Messina, Giuliana, Gellera, Cinzia, Previtali, Roberto, Veggiotti, Pierangelo, Milanesi, Raffaella, Barbuti, Andrea, Solazzi, Roberta, Freri, Elena, Granata, Tiziana, and Rivolta, Ilaria
- Abstract
Missense variants of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels cause variable phenotypes, ranging from mild generalized epilepsy to developmental and epileptic encephalopathy (DEE). Although variants of HCN1 are an established cause of DEE, those of HCN2 have been reported in generalized epilepsies. Here we describe the first case of DEE caused by the novel de novo heterozygous missense variant c.1379G>A (p.G460D) of HCN2. Functional characterization in transfected HEK293 cells and neonatal rat cortical neurons revealed that HCN2 p.G460D currents were strongly reduced compared to wild-type, consistent with a dominant negative loss-of-function effect. Immunofluorescence staining showed that mutant channels are retained within the cell and do not reach the membrane. Moreover, mutant HCN2 also affect HCN1 channels, by reducing the Ih current expressed by the HCN1-HCN2 heteromers. Due to the persistence of frequent seizures despite pharmacological polytherapy, the patient was treated with a ketogenic diet, with a significant and long-lasting reduction of episodes. In vitro experiments conducted in a ketogenic environment demonstrated that the clinical improvement observed with this dietary regimen was not mediated by a direct action on HCN2 activity. These results expand the clinical spectrum related to HCN2 channelopathies, further broadening our understanding of the pathogenesis of DEE.
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- 2023
6. Acetylation mediates Cx43 reduction caused by electrical stimulation
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Meraviglia, Viviana, Azzimato, Valerio, Colussi, Claudia, Florio, Maria Cristina, Binda, Anna, Panariti, Alice, Qanud, Khaled, Suffredini, Silvia, Gennaccaro, Laura, Miragoli, Michele, Barbuti, Andrea, Lampe, Paul D., Gaetano, Carlo, Pramstaller, Peter P., Capogrossi, Maurizio C., Recchia, Fabio A., Pompilio, Giulio, Rivolta, Ilaria, and Rossini, Alessandra
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- 2015
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7. SCN4A as modifier gene in patients with myotonic dystrophy type 2
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Binda, Anna, Renna, Laura V., Bosè, Francesca, Brigonzi, Elisa, Botta, Annalisa, Valaperta, Rea, Fossati, Barbara, Rivolta, Ilaria, Meola, Giovanni, and Cardani, Rosanna
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- 2018
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8. Functional Characterization of Two Variants at the Intron 6—Exon 7 Boundary of the KCNQ2 Potassium Channel Gene Causing Distinct Epileptic Phenotypes
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Mosca, Ilaria, primary, Rivolta, Ilaria, additional, Labalme, Audrey, additional, Ambrosino, Paolo, additional, Castellotti, Barbara, additional, Gellera, Cinzia, additional, Granata, Tiziana, additional, Freri, Elena, additional, Binda, Anna, additional, Lesca, Gaetan, additional, DiFrancesco, Jacopo C., additional, Soldovieri, Maria Virginia, additional, and Taglialatela, Maurizio, additional
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- 2022
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9. Do the functional properties of HCN1 mutants correlate with the clinical features in epileptic patients?
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Porro, Alessandro, primary, Abbandonato, Gerardo, additional, Veronesi, Valentina, additional, Russo, Alberto, additional, Binda, Anna, additional, Antolini, Laura, additional, Granata, Tiziana, additional, Castellotti, Barbara, additional, Marini, Carla, additional, Moroni, Anna, additional, DiFrancesco, Jacopo C., additional, and Rivolta, Ilaria, additional
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- 2021
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10. Binary Biocompatible CNC–Gelatine Hydrogel as 3D Scaffolds Suitable for Cell Culture Adhesion and Growth
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Zoia, Luca, primary, Binda, Anna, additional, Cipolla, Laura, additional, Rivolta, Ilaria, additional, and La Ferla, Barbara, additional
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- 2021
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11. Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths
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Monasky, M, Micaglio, E, Ciconte, G, Rivolta, I, Borrelli, V, Ghiroldi, A, D'Imperio, S, Binda, A, Melgari, D, Benedetti, S, Mitrovic, P, Anastasia, L, Mecarocci, V, Ćalović, Ž, Casari, G, Pappone, C, Monasky, Michelle M, Micaglio, Emanuele, Ciconte, Giuseppe, Rivolta, Ilaria, Borrelli, Valeria, Ghiroldi, Andrea, D'Imperio, Sara, Binda, Anna, Melgari, Dario, Benedetti, Sara, Mitrovic, Predrag, Anastasia, Luigi, Mecarocci, Valerio, Ćalović, Žarko, Casari, Giorgio, Pappone, Carlo, Monasky, M, Micaglio, E, Ciconte, G, Rivolta, I, Borrelli, V, Ghiroldi, A, D'Imperio, S, Binda, A, Melgari, D, Benedetti, S, Mitrovic, P, Anastasia, L, Mecarocci, V, Ćalović, Ž, Casari, G, Pappone, C, Monasky, Michelle M, Micaglio, Emanuele, Ciconte, Giuseppe, Rivolta, Ilaria, Borrelli, Valeria, Ghiroldi, Andrea, D'Imperio, Sara, Binda, Anna, Melgari, Dario, Benedetti, Sara, Mitrovic, Predrag, Anastasia, Luigi, Mecarocci, Valerio, Ćalović, Žarko, Casari, Giorgio, and Pappone, Carlo
- Abstract
Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T>A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.
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- 2021
12. Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths
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Monasky, Michelle M., primary, Micaglio, Emanuele, additional, Ciconte, Giuseppe, additional, Rivolta, Ilaria, additional, Borrelli, Valeria, additional, Ghiroldi, Andrea, additional, D’Imperio, Sara, additional, Binda, Anna, additional, Melgari, Dario, additional, Benedetti, Sara, additional, Mitrovic, Predrag, additional, Anastasia, Luigi, additional, Mecarocci, Valerio, additional, Ćalović, Žarko, additional, Casari, Giorgio, additional, and Pappone, Carlo, additional
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- 2021
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13. Effect of the ketogenic diet in excitable tissues
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Murano, Carmen, primary, Binda, Anna, additional, Palestini, Paola, additional, Baruscotti, Mirko, additional, DiFrancesco, Jacopo C., additional, and Rivolta, Ilaria, additional
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- 2021
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14. Innovative Therapies and Nanomedicine Applications for the Treatment of Alzheimer’s Disease: A State-of-the-Art (2017–2020)
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Binda,Anna, Murano,Carmen, and Rivolta,Ilaria
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International Journal of Nanomedicine - Abstract
Anna Binda,1 Carmen Murano,1 Ilaria Rivolta2 1School of Medicine and Surgery, University of Milano-Bicocca, Monza (MB) 20900, Italy; 2School of Medicine and Surgery, Nanomedicine Center NANOMIB, NeuroMI Milan Center for Neuroscience, University of Milano-Bicocca, Monza (MB) 20900, ItalyCorrespondence: Ilaria Rivolta Tel +39 2 64488319Email ilaria.rivolta@unimib.itAbstract: The field of nanomedicine is constantly expanding. Since the first work dated in 1999, almost 28 thousand articles have been published, and more and more are published every year: just think that only in the last five years 20,855 have come out (source PUBMED) including original research and reviews. The goal of this review is to present the current knowledge about nanomedicine in Alzheimer’s disease, a widespread neurodegenerative disorder in the over 60 population that deeply affects memory and cognition. Thus, after a brief introduction on the pathology and on the state-of-the-art research for NPs passing the BBB, special attention is placed to new targets that can enter the interest of nanoparticle designers and to new promising therapies. The authors performed a literature review limited to the last three years (2017– 2020) of available studies with the intention to present only novel formulations or approaches where at least in vitro studies have been performed. This choice was made because, while limiting the sector to nanotechnology applied to Alzheimer, an organic census of all the relevant news is difficult to obtain.Keywords: Alzheimer’s disease, therapy, nanomedicine, nanoparticles, nutraceutical, intranasal route, green synthesis, stem cells
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- 2020
15. Rational design of a mutation to investigate the role of the brain protein TRIP8b in limiting the cAMP response of HCN channels in neurons
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Porro, Alessandro, Binda, Anna, Pisoni, Matteo, Donadoni, Chiara, Rivolta, Ilaria, Saponaro, Andrea, Porro, A, Binda, A, Pisoni, M, Donadoni, C, Rivolta, I, and Saponaro, A
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Neurons ,Biophysics ,Brain ,Receptors, Cytoplasmic and Nuclear ,TRIP8b ,Biochemistry ,HCN ,Article ,Molecular Physiology ,channel trafficking ,Membrane Transport ,Mutation ,Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ,Ion Channel Gating - Abstract
The gating of neuronal HCN channels is modulated by the competitive binding of cAMP and TRIP8b, a brain-specific protein that also controls channel trafficking. Porro et al. identify a rational mutation in HCN channels that affects binding of TRIP8b, without altering cAMP affinity or TRIP8b-dependent trafficking. The mutation represents a valuable tool to investigate HCN channels in vivo., TRIP8b (tetratricopeptide repeat–containing Rab8b-interacting protein) is the neuronal regulatory subunit of HCN channels, a family of voltage-dependent cation channels also modulated by direct cAMP binding. TRIP8b interacts with the C-terminal region of HCN channels and controls both channel trafficking and gating. The association of HCN channels with TRIP8b is required for the correct expression and subcellular targeting of the channel protein in vivo. TRIP8b controls HCN gating by interacting with the cyclic nucleotide-binding domain (CNBD) and competing for cAMP binding. Detailed structural knowledge of the complex between TRIP8b and CNBD was used as a starting point to engineer a mutant channel, whose gating is controlled by cAMP, but not by TRIP8b, while leaving TRIP8b-dependent regulation of channel trafficking unaltered. We found two-point mutations (N/A and C/D) in the loop connecting the CNBD to the C-linker (N-bundle loop) that, when combined, strongly reduce the binding of TRIP8b to CNBD, leaving cAMP affinity unaltered both in isolated CNBD and in the full-length protein. Proof-of-principle experiments performed in cultured cortical neurons confirm that the mutant channel provides a genetic tool for dissecting the two effects of TRIP8b (gating versus trafficking). This will allow the study of the functional role of the TRIP8b antagonism of cAMP binding, a thus far poorly investigated aspect of HCN physiology in neurons.
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- 2020
16. Gabapentin treatment in a patient with KCNQ2 developmental epileptic encephalopathy
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Soldovieri, M, Freri, E, Ambrosino, P, Rivolta, I, Mosca, I, Binda, A, Murano, C, Ragona, F, Canafoglia, L, Vannicola, C, Solazzi, R, Granata, T, Castellotti, B, Messina, G, Gellera, C, Labalme, A, Lesca, G, Difrancesco, J, Taglialatela, M, Soldovieri, Maria Virginia, Freri, Elena, Ambrosino, Paolo, Rivolta, Ilaria, Mosca, Ilaria, Binda, Anna, Murano, Carmen, Ragona, Francesca, Canafoglia, Laura, Vannicola, Chiara, Solazzi, Roberta, Granata, Tiziana, Castellotti, Barbara, Messina, Giuliana, Gellera, Cinzia, Labalme, Audrey, Lesca, Gaetan, DiFrancesco, Jacopo C., Taglialatela, Maurizio, Soldovieri, M, Freri, E, Ambrosino, P, Rivolta, I, Mosca, I, Binda, A, Murano, C, Ragona, F, Canafoglia, L, Vannicola, C, Solazzi, R, Granata, T, Castellotti, B, Messina, G, Gellera, C, Labalme, A, Lesca, G, Difrancesco, J, Taglialatela, M, Soldovieri, Maria Virginia, Freri, Elena, Ambrosino, Paolo, Rivolta, Ilaria, Mosca, Ilaria, Binda, Anna, Murano, Carmen, Ragona, Francesca, Canafoglia, Laura, Vannicola, Chiara, Solazzi, Roberta, Granata, Tiziana, Castellotti, Barbara, Messina, Giuliana, Gellera, Cinzia, Labalme, Audrey, Lesca, Gaetan, DiFrancesco, Jacopo C., and Taglialatela, Maurizio
- Abstract
De novo variants in KCNQ2 encoding for Kv7.2 voltage-dependent neuronal potassium (K+) channel subunits are associated with developmental epileptic encephalopathy (DEE). We herein describe a the clinical and electroencephalographic (EEG) features of a child with early-onset DEE caused by the novel KCNQ2 p.G310S variant. In vitro experiments demonstrated that the mutation induces loss-of-function effects on the currents produced by channels incorporating mutant subunits; these effects were counteracted by the selective Kv7 opener retigabine and by gabapentin, a recently described Kv7 activator. Given these data, the patient started treatment with gabapentin, showing a rapid and sustained clinical and EEG improvement over the following months. Overall, these results suggest that gabapentin can be regarded as a precision therapy for DEEs due to KCNQ2 loss-of-function mutations.
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- 2020
17. GSTM3 variant is a novel genetic modifier in Brugada syndrome, a disease with risk of sudden cardiac death
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Juang, J, Binda, A, Lee, S, Hwang, J, Chen, W, Liu, Y, Lin, L, Yu, C, Ho, L, Huang, H, Chen, C, Lu, T, Lai, L, Yeh, S, Chuang, E, Rivolta, I, Antzelevitch, C, Juang, Jyh-Ming Jimmy, Binda, Anna, Lee, Shyh-Jye, Hwang, Juey-Jen, Chen, Wen-Jone, Liu, Yen-Bin, Lin, Lian-Yu, Yu, Chih-Chieh, Ho, Li-Ting, Huang, Hui-Chun, Chen, Ching-Yu Julius, Lu, Tzu-Pin, Lai, Liang-Chuan, Yeh, Shih-Fan Sherri, Lai, Ling-Ping, Chuang, Eric Y., Rivolta, Ilaria, Antzelevitch, Charles, Juang, J, Binda, A, Lee, S, Hwang, J, Chen, W, Liu, Y, Lin, L, Yu, C, Ho, L, Huang, H, Chen, C, Lu, T, Lai, L, Yeh, S, Chuang, E, Rivolta, I, Antzelevitch, C, Juang, Jyh-Ming Jimmy, Binda, Anna, Lee, Shyh-Jye, Hwang, Juey-Jen, Chen, Wen-Jone, Liu, Yen-Bin, Lin, Lian-Yu, Yu, Chih-Chieh, Ho, Li-Ting, Huang, Hui-Chun, Chen, Ching-Yu Julius, Lu, Tzu-Pin, Lai, Liang-Chuan, Yeh, Shih-Fan Sherri, Lai, Ling-Ping, Chuang, Eric Y., Rivolta, Ilaria, and Antzelevitch, Charles
- Abstract
Background: Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications. Methods: We enrolled 335 unrelated BrS patients from 2000 to 2018 in the Taiwanese population. Microarray and exome sequencing were used for discovery phase whereas Sanger sequencing was used for the validation phase. HEK cells and zebrafish were used to characterize the function of the CNV variant. Findings: A copy number deletion of GSTM3 (chr1:109737011-109737301, hg38) containing the eighth exon and the transcription stop codon was observed in 23.9% of BrS patients versus 0.8% of 15,829 controls in Taiwan Biobank (P < 0.001), and 0% in gnomAD. Co-segregation analysis showed that the co-segregation rate was 20%. Patch clamp experiments showed that in an oxidative stress environment, GSTM3 down-regulation leads to a significant decrease of cardiac sodium channel current amplitude. Ventricular arrhythmia incidence was significantly greater in gstm3 knockout zebrafish at baseline and after flecainide, but was reduced after quinidine, consistent with clinical observations. BrS patients carrying the GSTM3 deletion had higher rates of sudden cardiac arrest and syncope compared to those without (OR: 3.18 (1.77–5.74), P<0.001; OR: 1.76 (1.02–3.05), P = 0.04, respectively). Interpretation: This GSTM3 deletion is frequently observed in BrS patients and is associated with reduced INa, pointing to this as a novel potential genetic modifier/risk predictor for the development of the electrocardiographic and arrhythmic manifestations of BrS. Funding: This work was supported by the Ministry of Science and Technology (107-2314-B-002-261-MY3 to J.M.J. Juang), and by grants HL47678, HL138103 and HL152201 from the National Institutes of Health to CA.
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- 2020
18. Rational design of a mutation to investigate the role of the brain protein TRIP8b in limiting the cAMP response of HCN channels in neurons
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Porro, A, Binda, A, Pisoni, M, Donadoni, C, Rivolta, I, Saponaro, A, Porro, Alessandro, Binda, Anna, Pisoni, Matteo, Donadoni, Chiara, Rivolta, Ilaria, Saponaro, Andrea, Porro, A, Binda, A, Pisoni, M, Donadoni, C, Rivolta, I, Saponaro, A, Porro, Alessandro, Binda, Anna, Pisoni, Matteo, Donadoni, Chiara, Rivolta, Ilaria, and Saponaro, Andrea
- Abstract
TRIP8b (tetratricopeptide repeat-containing Rab8b-interacting protein) is the neuronal regulatory subunit of HCN channels, a family of voltage-dependent cation channels also modulated by direct cAMP binding. TRIP8b interacts with the C-terminal region of HCN channels and controls both channel trafficking and gating. The association of HCN channels with TRIP8b is required for the correct expression and subcellular targeting of the channel protein in vivo. TRIP8b controls HCN gating by interacting with the cyclic nucleotide-binding domain (CNBD) and competing for cAMP binding. Detailed structural knowledge of the complex between TRIP8b and CNBD was used as a starting point to engineer a mutant channel, whose gating is controlled by cAMP, but not by TRIP8b, while leaving TRIP8b-dependent regulation of channel trafficking unaltered. We found two-point mutations (N/A and C/D) in the loop connecting the CNBD to the C-linker (N-bundle loop) that, when combined, strongly reduce the binding of TRIP8b to CNBD, leaving cAMP affinity unaltered both in isolated CNBD and in the full-length protein. Proof-of-principle experiments performed in cultured cortical neurons confirm that the mutant channel provides a genetic tool for dissecting the two effects of TRIP8b (gating versus trafficking). This will allow the study of the functional role of the TRIP8b antagonism of cAMP binding, a thus far poorly investigated aspect of HCN physiology in neurons.
- Published
- 2020
19. Cardiac and neuronal HCN channelopathies
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Rivolta, I, Binda, A, Masi, A, Difrancesco, J, Rivolta, Ilaria, Binda, Anna, Masi, Alessio, DiFrancesco, Jacopo C, Rivolta, I, Binda, A, Masi, A, Difrancesco, J, Rivolta, Ilaria, Binda, Anna, Masi, Alessio, and DiFrancesco, Jacopo C
- Abstract
Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are expressed as four different isoforms (HCN1-4) in the heart and in the central and peripheral nervous systems. In the voltage range of activation, HCN channels carry an inward current mediated by Na+ and K+, termed If in the heart and Ih in neurons. Altered function of HCN channels, mainly HCN4, is associated with sinus node dysfunction and other arrhythmias such as atrial fibrillation, ventricular tachycardia, and atrioventricular block. In recent years, several data have also shown that dysfunctional HCN channels, in particular HCN1, but also HCN2 and HCN4, can play a pathogenic role in epilepsy; these include experimental data from animal models, and data collected over genetic mutations of the channels identified and characterized in epileptic patients. In the central nervous system, alteration of the Ih current could predispose to the development of neurodegenerative diseases such as Parkinson’s disease; since HCN channels are widely expressed in the peripheral nervous system, their dysfunctional behavior could also be associated with the pathogenesis of neuropathic pain. Given the fundamental role played by the HCN channels in the regulation of the discharge activity of cardiac and neuronal cells, the modulation of their function for therapeutic purposes is under study since it could be useful in various pathological conditions. Here we review the present knowledge of the HCN-related channelopathies in cardiac and neurological diseases, including clinical, genetic, therapeutic, and physiopathological aspects.
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- 2020
20. Gabapentin treatment in a patient with KCNQ2 developmental epileptic encephalopathy
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Soldovieri, Maria Virginia, primary, Freri, Elena, additional, Ambrosino, Paolo, additional, Rivolta, Ilaria, additional, Mosca, Ilaria, additional, Binda, Anna, additional, Murano, Carmen, additional, Ragona, Francesca, additional, Canafoglia, Laura, additional, Vannicola, Chiara, additional, Solazzi, Roberta, additional, Granata, Tiziana, additional, Castellotti, Barbara, additional, Messina, Giuliana, additional, Gellera, Cinzia, additional, Labalme, Audrey, additional, Lesca, Gaetan, additional, DiFrancesco, Jacopo C., additional, and Taglialatela, Maurizio, additional
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- 2020
- Full Text
- View/download PDF
21. Badania i rozwój: Zaskoczyć klienta – techniki wykorzystywane przez branżę perfumeryjną
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Binda, Anna, primary
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- 2020
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22. GSTM3 variant is a novel genetic modifier in Brugada syndrome, a disease with risk of sudden cardiac death
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Juang, Jyh-Ming Jimmy, primary, Binda, Anna, additional, Lee, Shyh-Jye, additional, Hwang, Juey-Jen, additional, Chen, Wen-Jone, additional, Liu, Yen-Bin, additional, Lin, Lian-Yu, additional, Yu, Chih-Chieh, additional, Ho, Li-Ting, additional, Huang, Hui-Chun, additional, Chen, Ching-Yu Julius, additional, Lu, Tzu-Pin, additional, Lai, Liang-Chuan, additional, Yeh, Shih-Fan Sherri, additional, Lai, Ling-Ping, additional, Chuang, Eric Y., additional, Rivolta, Ilaria, additional, and Antzelevitch, Charles, additional
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- 2020
- Full Text
- View/download PDF
23. HCN ion channels and accessory proteins in epilepsy: genetic analysis of a large cohort of patients and review of the literature
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Difrancesco, J, Castellotti, B, Milanesi, R, Ragona, F, Freri, E, Canafoglia, L, Franceschetti, S, Ferrarese, C, Magri, S, Taroni, F, Costa, C, Labate, A, Gambardella, A, Solazzi, R, Binda, A, Rivolta, I, Di Gennaro, G, Casciato, S, D'Incerti, L, Barbuti, A, Difrancesco, D, Granata, T, Gellera, C, DiFrancesco, Jacopo C., Castellotti, Barbara, Milanesi, Raffaella, Ragona, Francesca, Freri, Elena, Canafoglia, Laura, Franceschetti, Silvana, Ferrarese, Carlo, Magri, Stefania, Taroni, Franco, Costa, Cinzia, Labate, Angelo, Gambardella, Antonio, Solazzi, Roberta, Binda, Anna, Rivolta, Ilaria, Di Gennaro, Giancarlo, Casciato, Sara, D'Incerti, Ludovico, Barbuti, Andrea, DiFrancesco, Dario, Granata, Tiziana, Gellera, Cinzia, Difrancesco, J, Castellotti, B, Milanesi, R, Ragona, F, Freri, E, Canafoglia, L, Franceschetti, S, Ferrarese, C, Magri, S, Taroni, F, Costa, C, Labate, A, Gambardella, A, Solazzi, R, Binda, A, Rivolta, I, Di Gennaro, G, Casciato, S, D'Incerti, L, Barbuti, A, Difrancesco, D, Granata, T, Gellera, C, DiFrancesco, Jacopo C., Castellotti, Barbara, Milanesi, Raffaella, Ragona, Francesca, Freri, Elena, Canafoglia, Laura, Franceschetti, Silvana, Ferrarese, Carlo, Magri, Stefania, Taroni, Franco, Costa, Cinzia, Labate, Angelo, Gambardella, Antonio, Solazzi, Roberta, Binda, Anna, Rivolta, Ilaria, Di Gennaro, Giancarlo, Casciato, Sara, D'Incerti, Ludovico, Barbuti, Andrea, DiFrancesco, Dario, Granata, Tiziana, and Gellera, Cinzia
- Abstract
The Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are highly expressed in the Central Nervous Systems, where they are responsible for the I h current. Together with specific accessory proteins, these channels finely regulate neuronal excitability and discharge activity. In the last few years, a substantial body of evidence has been gathered showing that modifications of I h can play an important role in the pathogenesis of epilepsy. However, the extent to which HCN dysfunction is spread among the epileptic population is still unknown. The aim of this work is to evaluate the impact of genetic mutations potentially affecting the HCN channels’ activity, using a NGS approach. We screened a large cohort of patients with epilepsy of unknown etiology for mutations in HCN1, HCN2 and HCN4 and in genes coding for accessory proteins (MiRP1, Filamin A, Caveolin-3, TRIP8b, Tamalin, S-SCAM and Mint2). We confirmed the presence of specific mutations of HCN genes affecting channel function and predisposing to the development of the disease. We also found several previously unreported additional genetic variants, whose contribution to the phenotype remains to be clarified. According to these results and data from literature, alteration of HCN1 channel function seems to play a major role in epilepsy, but also dysfunctional HCN2 and HCN4 channels can predispose to the development of the disease. Our findings suggest that inclusion of the genetic screening of HCN channels in diagnostic procedures of epileptic patients should be recommended. This would help pave the way for a better understanding of the role played by I h dysfunction in the pathogenesis of epilepsy.
- Published
- 2019
24. Modulation of the intrinsic neuronal excitability by multifunctional liposomes tailored for treatment of Alzheimer’s disease
- Author
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Binda, Anna, Panariti, Alice, Barbuti, Andrea, Murano, Carmen, Dal Magro, Roberta, Masserini, Massimo, Re, Francesca, Rivolta, Ilaria, Binda, A, Panariti, A, Barbuti, A, Murano, C, Dal Magro, R, Masserini, M, Re, F, and Rivolta, I
- Subjects
Male ,Neurons ,β-amyloid peptide ,Amyloid beta-Peptides ,Cell Survival ,Action Potentials ,Phosphatidic Acids ,Biocompatible Materials ,electrophysiology ,nanomedicine ,patch clamp ,Endocytosis ,Rats ,Mice ,action potential ,Apolipoproteins E ,Animals, Newborn ,Alzheimer Disease ,neurodegenerative disorders ,Liposomes ,Animals ,Nanoparticles ,neurodegenerative disorders, nanomedicine, action potential, electrophysiology, patch clamp, β-amyloid peptide ,Cells, Cultured ,Original Research - Abstract
Purpose Nanotechnologies turned out to be promising in the development of diagnostic and therapeutic approaches toward neurodegenerative disorders. However, only a very scant number of nanodevices until now proved to be effective on preclinical animal models. Although specific tests in vivo are available to assess the potential toxicity of these nanodevices on cognitive functions, those to evaluate their biosafety in vitro on neurons are still to be improved. Materials and methods We utilized the patch-clamp technique on primary cultures of cortical neural cells isolated from neonatal rats, aiming to evaluate their electrical properties after the incubation with liposomes (mApoE-PA-LIPs), previously proved able to cross the blood–brain barrier and to be effective on mouse models of Alzheimer’s disease (AD), both in the absence and in the presence of β-amyloid peptide oligomers. Results Data show a high degree of biocompatibility, evaluated by lactate dehydrogenase (LDH) release and MTT assay, and the lack of cellular internalization. After the incubation with mApoE-PA-LIPs, neuronal membranes show an increase in the input resistance (from 724.14±76 MΩ in untreated population to 886.06±86 MΩ in the treated one), a reduction in the rheobase current (from 29.6±3 to 24.2±3 pA in untreated and treated, respectively), and an increase of the firing frequency, consistent with an ultimate increase in intrinsic excitability. Data obtained after co-incubation of mApoE-PA-LIPs with β-amyloid peptide oligomers suggest a retention of liposome efficacy. Conclusion These data suggest the ability of liposomes to modulate neuronal electrical properties and are compatible with the previously demonstrated amelioration of cognitive functions induced by treatment of AD mice with liposomes. We conclude that this electrophysiological approach could represent a useful tool for nanomedicine to evaluate the effect of nanoparticles on intrinsic neuronal excitability.
- Published
- 2018
25. SCN4A as modifier gene in patients with myotonic dystrophy type 2
- Author
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Binda, A, Renna, L, Bose', F, Brigonzi, E, Botta, A, Valaperta, R, Fossati, B, Rivolta, I, Meola, G, Cardani, R, Binda, Anna, Renna, Laura V., BOSE', FRANCESCA, Brigonzi, Elisa, Botta, Annalisa, Valaperta, Rea, Fossati, Barbara, Rivolta, Ilaria, Meola, Giovanni, Cardani, Rosanna, Binda, A, Renna, L, Bose', F, Brigonzi, E, Botta, A, Valaperta, R, Fossati, B, Rivolta, I, Meola, G, Cardani, R, Binda, Anna, Renna, Laura V., BOSE', FRANCESCA, Brigonzi, Elisa, Botta, Annalisa, Valaperta, Rea, Fossati, Barbara, Rivolta, Ilaria, Meola, Giovanni, and Cardani, Rosanna
- Abstract
A patient with an early severe myotonia diagnosed for Myotonic Dystrophy type 2 (DM2) was found bearing the combined effects of DM2 mutation and Nav1.4 S906T substitution. To investigate the mechanism underlying his atypical phenotype,whole-cell patch-clamp in voltage- and current-clamp mode was performed in myoblasts and myotubes obtained from his muscle biopsy. Results characterizing the properties of the sodium current and of the action potentials have been compared to those obtained in muscle cells derived from his mother, also affected by DM2, but without the S906T polymorphism. A faster inactivation kinetics and a +5 mV shift in the availability curve were found in the sodium current recorded in patient’s myoblasts compared to his mother. 27% of his myotubes displayed spontaneous activity. Patient’s myotubes showing a stable resting membrane potential had a lower rheobase current respect to the mother’s while the overshoot and the maximum slope of the depolarizing phase of action potential were higher. These findings suggest that SCN4A polymorphisms may be responsible for a higher excitability of DM2 patients sarcolemma, supporting the severe myotonic phenotype observed. We suggest SCN4A as a modifier factor and that its screening should be performed in DM2 patients with uncommon clinical features
- Published
- 2018
26. A novel KCNJ2 mutation identified in an autistic proband affects the single channel properties of Kir2.1
- Author
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Binda, A, Rivolta, I, Villa, C, Chisci, E, Beghi, M, Cornaggia, C, Giovannoni, R, Combi, R, Binda, Anna, Rivolta, Ilaria, Villa, Chiara, Chisci, Elisa, Beghi, Massimiliano, Cornaggia, Cesare M., Giovannoni, Roberto, Combi, Romina, Binda, A, Rivolta, I, Villa, C, Chisci, E, Beghi, M, Cornaggia, C, Giovannoni, R, Combi, R, Binda, Anna, Rivolta, Ilaria, Villa, Chiara, Chisci, Elisa, Beghi, Massimiliano, Cornaggia, Cesare M., Giovannoni, Roberto, and Combi, Romina
- Abstract
Inwardly rectifying potassium channels (Kir) have been historically associated to several cardiovascular disorders. In particular, loss-of-function mutations in the Kir2.1 channel have been reported in cases affected by Andersen-Tawil syndrome while gain-of-function mutations in the same channel cause the short QT3 syndrome. Recently, a missense mutation in Kir2.1, as well as mutations in the Kir4.1, were reported to be involved in autism spectrum disorders (ASDs) suggesting a role of potassium channels in these diseases and introducing the idea of the existence of K+ channel ASDs. Here, we report the identification in an Italian affected family of a novel missense mutation (p.Phe58Ser) in the KCNJ2 gene detected in heterozygosity in a proband affected by autism and borderline for short QT syndrome type 3. The mutation is located in the N-terminal region of the gene coding for the Kir2.1 channel and in particular in a very conserved domain. In vitro assays demonstrated that this mutation results in an increase of the channel conductance and in its open probability. This gain-of-function of the protein is consistent with the autistic phenotype, which is normally associated to an altered neuronal excitability.
- Published
- 2018
27. Modulation of the intrinsic neuronal excitability by multifunctional liposomes tailored for the treatment of Alzheimer's disease
- Author
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Binda,Anna, Panariti,Alice, Barbuti,Andrea, Murano,Carmen, Dal Magro,Roberta, Masserini,Massimo, Re,Francesca, Rivolta,Ilaria, Binda,Anna, Panariti,Alice, Barbuti,Andrea, Murano,Carmen, Dal Magro,Roberta, Masserini,Massimo, Re,Francesca, and Rivolta,Ilaria
- Abstract
Anna Binda,1 Alice Panariti,1 Andrea Barbuti,2 Carmen Murano,1 Roberta Dal Magro,1 Massimo Masserini,1,3,4 Francesca Re,1,3,4 Ilaria Rivolta,1,3,4 1School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; 2Department of Biosciences, The PaceLab and Interuniversity Center of Molecular Medicine and Applied Biophysics (CIMMBA), University of Milan, Milano, Italy; 3Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Monza, Italy; 4Nanomedicine Center NANOMIB, University of Milano-Bicocca, Milano, Italy Purpose: Nanotechnologies turned out to be promising in the development of diagnostic and therapeutic approaches toward neurodegenerative disorders. However, only a very scant number of nanodevices until now proved to be effective on preclinical animal models. Although specific tests in vivo are available to assess the potential toxicity of these nanodevices on cognitive functions, those to evaluate their biosafety in vitro on neurons are still to be improved. Materials and methods: We utilized the patch-clamp technique on primary cultures of cortical neural cells isolated from neonatal rats, aiming to evaluate their electrical properties after the incubation with liposomes (mApoE-PA-LIPs), previously proved able to cross the blood–brain barrier and to be effective on mouse models of Alzheimer’s disease (AD), both in the absence and in the presence of β-amyloid peptide oligomers. Results: Data show a high degree of biocompatibility, evaluated by lactate dehydrogenase (LDH) release and MTT assay, and the lack of cellular internalization. After the incubation with mApoE-PA-LIPs, neuronal membranes show an increase in the input resistance (from 724.14±76 MΩ in untreated population to 886.06±86 MΩ in the treated one), a reduction in the rheobase current (from 29.6±3 to 24.2±3 pA in untreated and treated, respectively), a
- Published
- 2018
28. SCN4A as modifier gene in myotonic dystrophy type 2 (DM2) patients with early and severe myotonia
- Author
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BINDA, ANNA, RIVOLTA, ILARIA, Cardani, R, Renna, LV, Fossati, B, Bosè, F, Botta, A, Valaperta, R, Meola, G, Binda, A, Cardani, R, Renna, L, Fossati, B, Bosè, F, Botta, A, Valaperta, R, Meola, G, and Rivolta, I
- Subjects
Myotonic dystrophy type 2, SCN4A, patch clamp ,BIO/09 - FISIOLOGIA - Abstract
Myotonia, mild and inconsistent in DM2, has been correlated with the disruption of the alternative splicing of CLCN1. Mutations in CLCN1 and SCN4A genes can act as modifiers in these patients leading to an amplification of their myotonic symptoms. A DM2 patient with an early severe myotonia came to our attention. No mutation was found on CLCN1 gene, but SCN4A gene showed G2717C base exchange, a variant considered a benign polymorphism. In the proband mother, also affected by DM2 but without the SCN4A polymorphism, no clinical myotonia was observed. The aim of the study was to compare the sodium current properties in myoblasts and the action potential features in myotubes derived from the proband and his mother muscle biopsies. Patch clamp was used for electrophysiological recordings. Preliminary results in myoblasts showed no change in the steady state activation properties but a significant shift in its availability curve (V1/2 -74±0,2 mV n=8 and V1/2 -79±0,2 mV n=9 proband and mother respectively); in myotubes, the minimum current necessary to elicit an action potential was lower in the proband than in his mother (272±6 pA n=9 and 462±130 pA, n=6), respectively. In conclusion we suggest that: SCN4A polymorphism may induce a more excitable substrate potentially aggravating the effect of the DM2 mutations; that SCN4A gene screening should be performed in DM2 patients with early and severe myotonia without mutations in CLCN1 gene, and finally that the detection of modifying factors may have important clinical implication such as the identification of appropriate drug treatment
- Published
- 2017
29. HCN1mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond
- Author
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Marini, Carla, primary, Porro, Alessandro, additional, Rastetter, Agnès, additional, Dalle, Carine, additional, Rivolta, Ilaria, additional, Bauer, Daniel, additional, Oegema, Renske, additional, Nava, Caroline, additional, Parrini, Elena, additional, Mei, Davide, additional, Mercer, Catherine, additional, Dhamija, Radhika, additional, Chambers, Chelsea, additional, Coubes, Christine, additional, Thévenon, Julien, additional, Kuentz, Paul, additional, Julia, Sophie, additional, Pasquier, Laurent, additional, Dubourg, Christèle, additional, Carré, Wilfrid, additional, Rosati, Anna, additional, Melani, Federico, additional, Pisano, Tiziana, additional, Giardino, Maria, additional, Innes, A Micheil, additional, Alembik, Yves, additional, Scheidecker, Sophie, additional, Santos, Manuela, additional, Figueiroa, Sonia, additional, Garrido, Cristina, additional, Fusco, Carlo, additional, Frattini, Daniele, additional, Spagnoli, Carlotta, additional, Binda, Anna, additional, Granata, Tiziana, additional, Ragona, Francesca, additional, Freri, Elena, additional, Franceschetti, Silvana, additional, Canafoglia, Laura, additional, Castellotti, Barbara, additional, Gellera, Cinzia, additional, Milanesi, Raffaella, additional, Mancardi, Maria Margherita, additional, Clark, Damien R, additional, Kok, Fernando, additional, Helbig, Katherine L, additional, Ichikawa, Shoji, additional, Sadler, Laurie, additional, Neupauerová, Jana, additional, Laššuthova, Petra, additional, Štěrbová, Katalin, additional, Laridon, Annick, additional, Brilstra, Eva, additional, Koeleman, Bobby, additional, Lemke, Johannes R, additional, Zara, Federico, additional, Striano, Pasquale, additional, Soblet, Julie, additional, Smits, Guillaume, additional, Deconinck, Nicolas, additional, Barbuti, Andrea, additional, DiFrancesco, Dario, additional, LeGuern, Eric, additional, Guerrini, Renzo, additional, Santoro, Bina, additional, Hamacher, Kay, additional, Thiel, Gerhard, additional, Moroni, Anna, additional, DiFrancesco, Jacopo C, additional, and Depienne, Christel, additional
- Published
- 2018
- Full Text
- View/download PDF
30. Modulation of the intrinsic neuronal excitability by multifunctional liposomes tailored for the treatment of Alzheimer's disease
- Author
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Binda, Anna, primary, Panariti, Alice, additional, Barbuti, Andrea, additional, Murano, Carmen, additional, Dal Magro, Roberta, additional, Masserini, Massimo, additional, Re, Francesca, additional, and Rivolta, Ilaria, additional
- Published
- 2018
- Full Text
- View/download PDF
31. A Novel KCNJ2 Mutation Identified in an Autistic Proband Affects the Single Channel Properties of Kir2.1
- Author
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Binda, Anna, primary, Rivolta, Ilaria, additional, Villa, Chiara, additional, Chisci, Elisa, additional, Beghi, Massimiliano, additional, Cornaggia, Cesare M., additional, Giovannoni, Roberto, additional, and Combi, Romina, additional
- Published
- 2018
- Full Text
- View/download PDF
32. Badania i rozwój: Manipulacja wielkością opakowania - sztuka downsizingu
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Binda, Anna, primary
- Published
- 2018
- Full Text
- View/download PDF
33. JMV5656, a novel derivative of TLQP-21, triggers the activation of a calcium-dependent potassium outward current in microglial cells
- Author
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Rivolta, I, Binda, A, Molteni, L, Rizzi, L, Bresciani, E, Possenti, R, Fehrentz, J, Verdié, P, Martinez, J, Omeljaniuk, R, Locatelli, V, Torsello, A, RIVOLTA, ILARIA, BINDA, ANNA, MOLTENI, LAURA, RIZZI, LAURA, BRESCIANI, ELENA, LOCATELLI, VITTORIO, TORSELLO, ANTONIO BIAGIO, Fehrentz, J. A, Omeljaniuk, RJ, Rivolta, I, Binda, A, Molteni, L, Rizzi, L, Bresciani, E, Possenti, R, Fehrentz, J, Verdié, P, Martinez, J, Omeljaniuk, R, Locatelli, V, Torsello, A, RIVOLTA, ILARIA, BINDA, ANNA, MOLTENI, LAURA, RIZZI, LAURA, BRESCIANI, ELENA, LOCATELLI, VITTORIO, TORSELLO, ANTONIO BIAGIO, Fehrentz, J. A, and Omeljaniuk, RJ
- Abstract
TLQP-21 (TLQPPASSRRRHFHHALPPAR) is a multifunctional peptide that is involved in the control of physiological functions, including feeding, reproduction, stress responsiveness, and general homeostasis. Despite the huge interest in TLQP-21 biological activity, very little is known about its intracellular mechanisms of action. In microglial cells, TLQP-21 stimulates increases of intracellular Ca2+ that may activate functions, including proliferation, migration, phagocytosis and production of inflammatory molecules. Our aim was to investigate whether JMV5656 (RRRHFHHALPPAR), a novel short analogue of TLQP-21, stimulates intracellular Ca2+ in the N9 microglia cells, and whether this Ca2+ elevation is coupled with the activation Ca2+ -sensitive K+ channels. TLQP-21 and JMV5656 induced a sharp, dose-dependent increment in intracellular calcium. In 77% of cells, JMV5656 also caused an increase in the total outward currents, which was blunted by TEA (tetraethyl ammonium chloride), a non-selective blocker of voltage-dependent and Ca2+ -activated potassium (K+) channels. Moreover, the effects of ion channel blockers charybdotoxin and iberiotoxin, suggested that multiple calcium-activated K+ channel types drove the outward current stimulated by JMV5656. Additionally, inhibition of JMV5656-stimulated outward currents by NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4 benzothiazin-3(4H)-one) and TRAM-34 (triarylmethane-34), indicated that KCa 3.1 channels are involved in this JMV5656 mechanisms of action. In summary, we demonstrate that, in N9 microglia cells, the interaction of JMV5656 with the TLQP-21 receptors induced an increase in intracellular Ca2+, and, following extracellular Ca2+ entry, the opening of KCa 3.1 channels.
- Published
- 2017
34. Relevance of electrolytic balance in channelopathies.
- Author
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Binda, A, RIVOLTA, ILARIA, BINDA, ANNA, Binda, A, RIVOLTA, ILARIA, and BINDA, ANNA
- Abstract
Il mio progetto di dottorato è legato allo studio di mutazioni geniche identificate in pazienti affetti da canalopatie, un gruppo molto eterogeneo di patologie che comprende i disordini a carico dei canali ionici. Poiché i canali ionici sono caratterizzati da un profilo di espressione differente e specifico nelle membrane delle cellule che compongono l’architettura dei vari tessuti, le canalopatie includono malattie del sistema nervoso, cardiovascolare, muscolare, respiratorio, endocrino, urinario e immunitario. La caratterizzazione funzionale dei canali ionici mutati ha lo scopo di comprendere i meccanismi patologici causa delle canalopatie. Durante il dottorato, mi sono occupata di caratterizzare mutazioni in diversi canali ionici associate a patologie differenti, in particolare, ho seguito progetti legati alla caratterizzazione funzionale di una mutazione nel gene SCN4A quale fattore modificante in un fenotipo di distrofia miotonica di tipo 2 (DM2), di una nuova mutazione nel gene KCNJ2 identificata in un paziente affetto da autismo, dello studio del ruolo di GSTM3 come gene modificatore in pazienti affetti da sindrome di Brugada e di una mutazione identificata nel gene KCNT1 in un paziente affetto da sindrome di Brugada., My PhD project focused on the theme of alterations of electrolytic balance as a consequence of disorders affecting ion channels, which are proteins expressed on the cellular membrane where they physiologically regulate ion concentrations between the intracellular compartment and the extracellular environment. Ion channels disorders are responsible for a group of heterogenic diseases, generally referred as “channelopathies”, that influence the nervous, the cardiovascular, the muscular, the respiratory, the endocrine, the immune or the urinary system. My project dealt with the functional characterization of mutations in genes encoding ion channels identified by collaborating groups in patients affected by different channelopathies. The properties of each mutant channel was compared to the relative wild type form in order to unravel the mechanisms underlying the disease. The mutations studied were a variant in the sodium channel gene SCN4A identified in a patient affected by myotonic dystrophy type 2 (DM2), a mutation in KCNJ2 gene, encoding for the inwardly rectifying potassium channel Kir2.1, identified in a patient affected by a form of autism, GSTM3 CNVs deletion in a cohort of patients affected by Brugada Syndrome and a mutation in KCNT1 gene, encoding for a sodium-dependent potassium channel, identified in a patient affected by Brugada Syndrome. All the single-nucleotide mutations were carried in heterozygosis by the patients. After selecting the most suitable cell line for each subproject, cells were transiently transfected with appropriate vectors to express the WT or the mutant form of the channel. 48 hours after the transfection, patch-clamp in whole cell configuration were performed and specific protocols were applied to characterize ion channels biophysical properties. Data were analyzed through a proper software.
- Published
- 2017
35. SCN4A as modifier gene in myotonic dystrophy type 2 (DM2) patients with early and severe myotonia
- Author
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Binda, A, Cardani, R, Renna, L, Fossati, B, Bosè, F, Botta, A, Valaperta, R, Meola, G, Rivolta, I, BINDA, ANNA, RIVOLTA, ILARIA, Renna, LV, Binda, A, Cardani, R, Renna, L, Fossati, B, Bosè, F, Botta, A, Valaperta, R, Meola, G, Rivolta, I, BINDA, ANNA, RIVOLTA, ILARIA, and Renna, LV
- Abstract
Myotonia, mild and inconsistent in DM2, has been correlated with the disruption of the alternative splicing of CLCN1. Mutations in CLCN1 and SCN4A genes can act as modifiers in these patients leading to an amplification of their myotonic symptoms. A DM2 patient with an early severe myotonia came to our attention. No mutation was found on CLCN1 gene, but SCN4A gene showed G2717C base exchange, a variant considered a benign polymorphism. In the proband mother, also affected by DM2 but without the SCN4A polymorphism, no clinical myotonia was observed. The aim of the study was to compare the sodium current properties in myoblasts and the action potential features in myotubes derived from the proband and his mother muscle biopsies. Patch clamp was used for electrophysiological recordings. Preliminary results in myoblasts showed no change in the steady state activation properties but a significant shift in its availability curve (V1/2 -74±0,2 mV n=8 and V1/2 -79±0,2 mV n=9 proband and mother respectively); in myotubes, the minimum current necessary to elicit an action potential was lower in the proband than in his mother (272±6 pA n=9 and 462±130 pA, n=6), respectively. In conclusion we suggest that: SCN4A polymorphism may induce a more excitable substrate potentially aggravating the effect of the DM2 mutations; that SCN4A gene screening should be performed in DM2 patients with early and severe myotonia without mutations in CLCN1 gene, and finally that the detection of modifying factors may have important clinical implication such as the identification of appropriate drug treatment
- Published
- 2017
36. 21st-century perfume flacons : contemporary trends in designing 'small works of art'
- Author
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Binda, Anna
- Subjects
opakowanie ,perfumy ,design ,perfume ,package ,perfume bottle ,flakon perfum - Abstract
Perfumy są stare jak świat. Od samego początku ogromną wagę przywiązywano do tego, w jaki sposób i w co są zapakowane. Ważne było, aby materiał, w jakim mieści się kompozycja zapachowa był najwyższej jakości. Współcześnie mamy wrażenie, że historia zatoczyła w tym obszarze koło. Flakony perfum stają się niejako manifestacją stylu projektanta, wewnętrzną myślą perfumiarza, istnym kryształowym dziełem rąk. W przypadku perfum, jak w żadnym innym segmencie kosmetycznym nie może być mowy o dysonansie pomiędzy opakowaniem, a tym co mieści się w jego wnętrzu. Nuta zapachowa musi perfekcyjnie współgrać z wyglądem flakonu - kształtem, a zarazem kolorystyką i grafiką. Na flakonie nie ma miejsca na nadmiar tekstu, dlatego całą uwagę koncentruje się na pozostałe zewnętrzne elementy - materiał, zamknięcie opakowania, jego kształt oraz kolorystykę. Bardzo często dzięki tego typu zabiegom flakon przemawia do nas jeszcze przed otwarciem, zanim poczujemy woń tego, co mieści w swoim wnętrzu. Współcześnie konsumenci traktują flakony jako szklaną ozdobę swoich półek. Co za tym idzie stają się one niejednokrotnie małymi dziełami sztuki. Producenci oraz projektanci opakowań zdają sobie doskonale sprawę z owego faktu. Idą zgodnie z duchem nowoczesnych trendów i oczekiwań konsumentów. Jakie są nowoczesne trendy i oczekiwania pasjonatów "świata perfumeryjnego" zostanie przedstawione w artykule. Perfumes are as old as the hills. Since the beginning, great attention has been paid to the way these aromatic compositions were packed. It was crucial for the material to be of the best quality. Today, it seems that history is coming full circle. Perfume flacons are becoming a demonstration of a designer's style, a perfumer’s inner thought, a veritable, crystal artifact. In the case of perfumes, a dissonance between their package and the content simply cannot appear. A fragrance note has to be perfectly consistent with the flacon, as well as its shape, color scheme, and graphics. Because there is no place for information overload on a label, a recipient’s attention is fully focused on other outer components, such as the material the flacon is made of, the package, its closing, shape and color scheme. Very often, due to this type of measures, the bottle itself appeals to us before we are able to smell the fragrance. Nowadays, consumers treat perfume flacons as an ornament that can be placed on a shelf. That is why they increasingly become small works of art. Manufacturers and designers are fully aware of this fact. They move with the times, and follow consumers' expectations. The modern trends and the expectations of the "fragrance world" enthusiasts have been presented in the article.
- Published
- 2016
37. BADANIA I ROZWÓJ: Miejsce opakowania w strategii marketingowej przedsiębiorstw sektora kosmetycznego
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BINDA, ANNA, primary
- Published
- 2017
- Full Text
- View/download PDF
38. Pharmacological and Biochemical Characterization of TLQP-21 Activation of a Binding Site on CHO Cells
- Author
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Molteni, Laura, primary, Rizzi, Laura, additional, Bresciani, Elena, additional, Possenti, Roberta, additional, Petrocchi Passeri, Pamela, additional, Ghè, Corrado, additional, Muccioli, Giampiero, additional, Fehrentz, Jean-Alain, additional, Verdié, Pascal, additional, Martinez, Jean, additional, Omeljaniuk, Robert J., additional, Biagini, Giuseppe, additional, Binda, Anna, additional, Rivolta, Ilaria, additional, Locatelli, Vittorio, additional, and Torsello, Antonio, additional
- Published
- 2017
- Full Text
- View/download PDF
39. JMV5656, A Novel Derivative of TLQP-21, Triggers the Activation of a Calcium-Dependent Potassium Outward Current in Microglial Cells
- Author
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Rivolta, Ilaria, primary, Binda, Anna, additional, Molteni, Laura, additional, Rizzi, Laura, additional, Bresciani, Elena, additional, Possenti, Roberta, additional, Fehrentz, Jean-Alain, additional, Verdié, Pascal, additional, Martinez, Jean, additional, Omeljaniuk, Robert J., additional, Locatelli, Vittorio, additional, and Torsello, Antonio, additional
- Published
- 2017
- Full Text
- View/download PDF
40. Flakony perfum na miarę XXI w. - współczesne trendy w projektowaniu "małych dzieł sztuki"
- Author
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BINDA, ANNA, primary
- Published
- 2016
- Full Text
- View/download PDF
41. Acetylation mediates Cx43 reduction caused by electrical stimulation
- Author
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Meraviglia, V, Azzimato, V, Colussi, C, Florio, M, Binda, A, Panariti, A, Qanud, K, Suffredini, S, Gennaccaro, L, Miragoli, M, Barbuti, A, Lampe, P, Gaetano, C, Pramstaller, P, Capogrossi, M, Recchia, F, Pompilio, G, Rivolta, I, Rossini, A, Florio, MC, BINDA, ANNA, PANARITI, ALICE LUCIA, Lampe, PD, Pramstaller, PP, Capogrossi, MC, Recchia, FA, RIVOLTA, ILARIA, Rossini, A., Meraviglia, V, Azzimato, V, Colussi, C, Florio, M, Binda, A, Panariti, A, Qanud, K, Suffredini, S, Gennaccaro, L, Miragoli, M, Barbuti, A, Lampe, P, Gaetano, C, Pramstaller, P, Capogrossi, M, Recchia, F, Pompilio, G, Rivolta, I, Rossini, A, Florio, MC, BINDA, ANNA, PANARITI, ALICE LUCIA, Lampe, PD, Pramstaller, PP, Capogrossi, MC, Recchia, FA, RIVOLTA, ILARIA, and Rossini, A.
- Abstract
Communication between cardiomyocytes depends upon gap junctions (GJ). Previous studies have demonstrated that electrical stimulation induces GJ remodeling and modifies histone acetylase (HAT) and deacetylase (HDAC) activities, although these two results have not been linked. The aim of this work was to establish whether electrical stimulation modulates GJ-mediated cardiac cell-cell communication by acetylation-dependent mechanisms. Field stimulation of HL-1 cardiomyocytes at 0.5. Hz for 24. h significantly reduced connexin43 (Cx43) expression and cell-cell communication. HDAC activity was down-regulated whereas HAT activity was not modified resulting in increased acetylation of Cx43. Consistent with a post-translational mechanism, we did not observe a reduction in Cx43 mRNA in electrically stimulated cells, while the proteasomal inhibitor MG132 maintained Cx43 expression. Further, the treatment of paced cells with the HAT inhibitor Anacardic Acid maintained both the levels of Cx43 and cell-cell communication. Finally, we observed increased acetylation of Cx43 in the left ventricles of dogs subjected to chronic tachypacing as a model of abnormal ventricular activation.In conclusion, our findings suggest that altered electrical activity can regulate cardiomyocyte communication by influencing the acetylation status of Cx43.
- Published
- 2015
42. SCN4A mutation as modifying factor of Myotonic Dystrophy Type 2 phenotype
- Author
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Bugiardini, E, Rivolta, I, Binda, A, Soriano Caminero, A, Cirillo, F, Cinti, A, Giovannoni, R, Botta, A, Cardani, R, Wicklund, M, Meola, G, RIVOLTA, ILARIA, BINDA, ANNA, CINTI, ALESSANDRO, GIOVANNONI, ROBERTO, Meola, G., Bugiardini, E, Rivolta, I, Binda, A, Soriano Caminero, A, Cirillo, F, Cinti, A, Giovannoni, R, Botta, A, Cardani, R, Wicklund, M, Meola, G, RIVOLTA, ILARIA, BINDA, ANNA, CINTI, ALESSANDRO, GIOVANNONI, ROBERTO, and Meola, G.
- Abstract
In myotonic dystrophy type 2 (DM2), an association has been reported between early and severe myotonia and recessive chloride channel (. CLCN1) mutations. No DM2 cases have been described with sodium channel gene (. SCN4A) mutations. The aim is to describe a DM2 patient with severe and early onset myotonia and co-occurrence of a novel missense mutation in SNC4A. A 26-year-old patient complaining of hand cramps and difficulty relaxing her hands after activity was evaluated at our department. Neurophysiology and genetic analysis for DM1, DM2, CLCN1 and SCN4A mutations were performed. Genetic testing was positive for DM2 (2650 CCTG repeat) and for a variant c.215C>T (p.Pro72Leu) in the SCN4A gene. The variation affects the cytoplasmic N terminus domain of Nav1.4, where mutations have never been reported. The biophysical properties of the mutant Nav1.4 channels were evaluated by whole-cell voltage-clamp analysis of heterologously expressed mutant channel in tsA201 cells. Electrophysiological studies of the P72L variant showed a hyperpolarizing shift (-5mV) of the voltage dependence of activation that may increase cell excitability. This case suggests that SCN4A mutations may enhance the myotonic phenotype of DM2 patients and should be screened for atypical cases with severe myotonia.
- Published
- 2015
43. Recycling and environmental protection : 'golden rules' for designing packages of cosmetic products
- Author
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Binda, Anna
- Subjects
opakowanie ,środowisko ,recykling ,designing ,package ,recycling ,projektowanie ,environment - Abstract
Projektując opakowania poza wymogami prawa, etyki trzeba mieć również na uwadze te, które związane są z ekologią. Coraz więcej konsumentów zaczyna poszukiwać opakowań, które poza tym, że będą atrakcyjne, innowacyjne, funkcjonalne, będą również bezpieczne i zgodne z wymaganiami, jakie stawiają ruchy ekologiczne. Co za tym idzie na sklepowych półkach pojawia się coraz więcej produktów pięknie opakowanych w materiały naturalnych surowców lub tworzywa, które można ponownie przetworzyć. Recykling, ochrona środowiska, czyli jednym słowem ekologia wydaje się być zatem wyróżnikiem naszych czasów. Projektanci opakowań stosując się do zasad, jakie niesie ona za sobą mogą w skuteczny sposób zdobywać przewagę konkurencyjną. Obserwując bowiem codziennie podejmowane wybory zakupowe konsumentów można wysunąć hipotezę, że stajemy się społeczeństwem coraz bardziej świadomym ekologicznie. While designing packages, one must take into considerations not only legal and ethical requirements, but also those related to ecology. More and more consumers are starting to look for packages which, apart from being attractive, innovative and functional, will also be safe and consistent with the requirements postulated by ecological movements. As a consequence, there appear more and more products which are beautifully packaged in materials made of naturals resources or in recyclable materials. Recycling, environmental protection or, to put it shortly, ecology, seems to be a distinguishing feature of our times. By applying to its norms, designers of packages can effectively gain a competitive advantage. Since, by observing everyday shopping choices made by consumers, it is justified to draw a conclusion that we are becoming a society that is more and more ecologically conscious.
- Published
- 2013
44. Study of the effects of nanoliposomes engineered for the treatment of Alzheimer's disease on the electrical activity of cortical neurons
- Author
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BINDA, ANNA, BANA, LAURA, PANARITI, ALICE LUCIA, MINNITI, STEFANIA, MASSERINI, MASSIMO ERNESTO, RE, FRANCESCA, RIVOLTA, ILARIA, Binda, A, Bana, L, Panariti, A, Minniti, S, Masserini, M, Re, F, and Rivolta, I
- Subjects
Cellular electrophysiology, nanomedicine, Alzheimer Disease - Published
- 2013
45. Study of the effects of nanoliposomes engineered for the treatment of Alzheimer's disease on the electrical activity of cortical neurons
- Author
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Binda, A, Bana, L, Panariti, A, Minniti, S, Masserini, M, Re, F, Rivolta, I, BINDA, ANNA, BANA, LAURA, PANARITI, ALICE LUCIA, MINNITI, STEFANIA, MASSERINI, MASSIMO ERNESTO, RE, FRANCESCA, RIVOLTA, ILARIA, Binda, A, Bana, L, Panariti, A, Minniti, S, Masserini, M, Re, F, Rivolta, I, BINDA, ANNA, BANA, LAURA, PANARITI, ALICE LUCIA, MINNITI, STEFANIA, MASSERINI, MASSIMO ERNESTO, RE, FRANCESCA, and RIVOLTA, ILARIA
- Published
- 2013
46. Plasmid vectors for selecting IS1-promoted deletions in cloned DNA: sequence analysis of the omega interposon
- Author
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Prentki, Pierre, primary, Binda, Anna, additional, and Epstein, Andrée, additional
- Published
- 1991
- Full Text
- View/download PDF
47. Functional Characterization of Two Variants at the Intron 6—Exon 7 Boundary of the KCNQ2 Potassium Channel Gene Causing Distinct Epileptic Phenotypes
- Author
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Ilaria Mosca, Ilaria Rivolta, Audrey Labalme, Paolo Ambrosino, Barbara Castellotti, Cinzia Gellera, Tiziana Granata, Elena Freri, Anna Binda, Gaetan Lesca, Jacopo C. DiFrancesco, Maria Virginia Soldovieri, Maurizio Taglialatela, Mosca, Ilaria, Rivolta, Ilaria, Labalme, Audrey, Ambrosino, Paolo, Castellotti, Barbara, Gellera, Cinzia, Granata, Tiziana, Freri, Elena, Binda, Anna, Lesca, Gaetan, Difrancesco, Jacopo C, Soldovieri, Maria Virginia, Taglialatela, Maurizio, Mosca, I, Rivolta, I, Labalme, A, Ambrosino, P, Castellotti, B, Gellera, C, Granata, T, Freri, E, Binda, A, Lesca, G, Difrancesco, J, Soldovieri, M, and Taglialatela, M
- Subjects
KCNQ2 ,Kv7.2 subunit ,Pharmacology ,Kv7.2 subunits ,alternative splicing ,calmodulin ,epileptic encephalopathy ,PIP2 ,Pharmacology (medical) - Abstract
Pathogenic variants in KCNQ2 encoding for Kv7.2 potassium channel subunits have been found in patients affected by widely diverging epileptic phenotypes, ranging from Self-Limiting Familial Neonatal Epilepsy (SLFNE) to severe Developmental and Epileptic Encephalopathy (DEE). Thus, understanding the pathogenic molecular mechanisms of KCNQ2 variants and their correlation with clinical phenotypes has a relevant impact on the clinical management of these patients. In the present study, the genetic, biochemical, and functional effects prompted by two variants, each found in a non-familial SLNE or a DEE patient but both affecting nucleotides at the KCNQ2 intron 6-exon 7 boundary, have been investigated to test whether and how they affected the splicing process and to clarify whether such mechanism might play a pathogenetic role in these patients. Analysis of KCNQ2 mRNA splicing in patient-derived lymphoblasts revealed that the SLNE-causing intronic variant (c.928-1G > C) impeded the use of the natural splice site, but lead to a 10-aa Kv7.2 in frame deletion (Kv7.2 p.G310Δ10); by contrast, the DEE-causing exonic variant (c.928G > A) only had subtle effects on the splicing process at this site, thus leading to the synthesis of a full-length subunit carrying the G310S missense variant (Kv7.2 p.G310S). Patch-clamp recordings in transiently-transfected CHO cells and primary neurons revealed that both variants fully impeded Kv7.2 channel function, and exerted strong dominant-negative effects when co-expressed with Kv7.2 and/or Kv7.3 subunits. Notably, Kv7.2 p.G310S, but not Kv7.2 p.G310Δ10, currents were recovered upon overexpression of the PIP2-synthesizing enzyme PIP5K, and/or CaM; moreover, currents from heteromeric Kv7.2/Kv7.3 channels incorporating either Kv7.2 mutant subunits were differentially regulated by changes in PIP2 availability, with Kv7.2/Kv7.2 G310S/Kv7.3 currents showing a greater sensitivity to PIP2 depletion when compared to those from Kv7.2/Kv7.2 G310Δ10/Kv7.3 channels. Altogether, these results suggest that the two variants investigated differentially affected the splicing process at the intron 6-exon 7 boundary, and led to the synthesis of Kv7.2 subunits showing a differential sensitivity to PIP2 and CaM regulation; more studies are needed to clarify how such different functional properties contribute to the widely-divergent clinical phenotypes.
- Published
- 2022
- Full Text
- View/download PDF
48. Effect of the ketogenic diet in excitable tissues.
- Author
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Murano C, Binda A, Palestini P, Baruscotti M, DiFrancesco JC, and Rivolta I
- Subjects
- Animals, Central Nervous System Diseases diet therapy, Central Nervous System Diseases metabolism, Central Nervous System Diseases physiopathology, Heart Diseases diet therapy, Heart Diseases metabolism, Heart Diseases physiopathology, Humans, Membrane Potentials, Muscular Diseases diet therapy, Muscular Diseases metabolism, Muscular Diseases physiopathology, Signal Transduction, 3-Hydroxybutyric Acid metabolism, Diet, Ketogenic adverse effects, Energy Metabolism, Muscle Fibers, Skeletal metabolism, Myocytes, Cardiac metabolism, Neurons metabolism
- Abstract
In the past decade, ketogenic diet (KD) has gained some popularity as a potential treatment for a wide range of diseases, including neurological and metabolic disorders, thanks to a beneficial role mainly related to its anti-inflammatory properties. The high-fat and carbohydrate-restricted regimen causes changes in the metabolism, leading, through the β-oxidation of fatty acids, to the hepatic production of ketone bodies (KBs), which are used by many extrahepatic tissues as energy fuels. Once synthetized, KBs are delivered through the systemic circulation to all the tissues of the organism, where they play pleiotropic roles acting directly and indirectly on various targets, and among them ion channels and neurotransmitters. Moreover, they can operate as signaling metabolites and epigenetic modulators. Therefore, it is inappropriate to consider that the KD regimen can improve the patients' clinical condition simply by means of specific and localized effects; rather, it is more correct to think that KBs affect the organism as a whole. In this review, we tried to summarize the recent knowledge of the effects of KBs on various tissues, with a particular attention on the excitable ones, namely the nervous system, heart, and muscles.
- Published
- 2021
- Full Text
- View/download PDF
49. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.
- Author
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Marini C, Porro A, Rastetter A, Dalle C, Rivolta I, Bauer D, Oegema R, Nava C, Parrini E, Mei D, Mercer C, Dhamija R, Chambers C, Coubes C, Thévenon J, Kuentz P, Julia S, Pasquier L, Dubourg C, Carré W, Rosati A, Melani F, Pisano T, Giardino M, Innes AM, Alembik Y, Scheidecker S, Santos M, Figueiroa S, Garrido C, Fusco C, Frattini D, Spagnoli C, Binda A, Granata T, Ragona F, Freri E, Franceschetti S, Canafoglia L, Castellotti B, Gellera C, Milanesi R, Mancardi MM, Clark DR, Kok F, Helbig KL, Ichikawa S, Sadler L, Neupauerová J, Laššuthova P, Šterbová K, Laridon A, Brilstra E, Koeleman B, Lemke JR, Zara F, Striano P, Soblet J, Smits G, Deconinck N, Barbuti A, DiFrancesco D, LeGuern E, Guerrini R, Santoro B, Hamacher K, Thiel G, Moroni A, DiFrancesco JC, and Depienne C
- Subjects
- Adolescent, Adult, Aged, Animals, CHO Cells, Child, Child, Preschool, Cricetulus, Electric Stimulation, Female, Genetic Association Studies, Humans, Infant, Male, Membrane Potentials genetics, Middle Aged, Models, Molecular, Mutagenesis, Site-Directed methods, Young Adult, Epilepsy, Generalized genetics, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels genetics, Mutation genetics, Potassium Channels genetics, Spasms, Infantile genetics
- Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.
- Published
- 2018
- Full Text
- View/download PDF
50. Babesiosis.
- Author
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Binda, Anna, Ph.D.
- Subjects
Fever ,Babesiosis ,Parasitic diseases ,Diarrhea - Abstract
ALSO KNOWN AS: Human piroplasmosis, Nantucket fever
- Published
- 2024
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