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1. Fifteen Years of Iodine Prophylaxis in Italy: Results of a Nationwide Surveillance (Period 2015-2019)

Author

De Angelis, Simona, Medda, Emanuela, Rotondi, Daniela, Masocco, Maria, Minardi, Valentina, Contoli, Benedetta, Possenti, Valentina, Sorbo, Angela, D’Amato, Marilena, Turco, Anna Chiara, Pastorelli, Alberto Augusto, Stacchini, Paolo, Cas, Roberto Da, Bagnasco, Marcello, Bonofiglio, Daniela, Gasperi, Maurizio, Meringolo, Domenico, Mian, Caterina, Moleti, Mariacarla, Vermiglio, Francesco, Puxeddu, Efisio, Taccaliti, Augusto, Tonacchera, Massimo, Ulisse, Salvatore, Dimida, Antonio, Rago, Teresa, Nazzari, Elena, Schiavo, Mara, Bossert, Irene, Sturniolo, Giacomo, Corbetta, Carlo, Cereda, Cristina, Cappelletti, Laura, Camilot, Marta, Teofoli, Francesca, Ciatti, Renzo, Tarsi, Elisabetta, Perrotti, Nicola, Marasco, Onorina, Scozzafava, Giovanna, Righetti, Francesca, Andò, Sebastiano, Catalano, Stefania, Cristofaro, Mariarosaria, Sorrenti, Giovanni, Censi, Simona, Morelli, Silvia, Baldini, Enke, Plutino, Giuseppe, Copparoni, Roberto, Alonzo, Elena, Giacomozzi, Claudia, Silano, Marco, and Olivieri, Antonella

Published
2024
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2. Bone Marrow Mesenchymal Stem Cells Expanded Inside the Nichoid Micro-Scaffold: a Focus on Anti-Inflammatory Response

Author

Barzaghini, Bianca, Carelli, Stephana, Messa, Letizia, Rey, Federica, Avanzini, Maria Antonietta, Jacchetti, Emanuela, Maghraby, Erika, Berardo, Clarissa, Zuccotti, Gianvincenzo, Raimondi, Manuela Teresa, Cereda, Cristina, Calcaterra, Valeria, and Pelizzo, Gloria

Abstract

Purpose: Mesenchymal stem cells (MSCs) represent a promising source for stem cell therapies in numerous diseases, including pediatric respiratory system diseases. Characterized by low immunogenicity, high anti-inflammatory, and immunoregulatory features, MSCs demonstrated an excellent therapeutic profile in numerous in vitro and preclinical models. MSCs reside in a specialized physiologic microenvironment, characterized by a unique combination of biophysical, biochemical, and cellular properties. The exploitation of the 3D micro-scaffold Nichoid, which simulates the native niche, enhanced the anti-inflammatory potential of stem cells through mechanical stimulation only, overcoming the limitation of biochemical and xenogenic growth factors application. Materials and Methods: In this work, we expanded pediatric bone marrow MSCs (BM-MSCs) inside the Nichoid and performed a complete cellular characterization with different approaches including viability assays, immunofluorescence analyses, RNA sequencing, and gene expression analysis. Results: We demonstrated that BM-MSCs inside the scaffold remain in a stem cell quiescent state mimicking the condition of the in vivo environment. Moreover, the gene expression profile of these cells shows a significant up-regulation of genes involved in immune response when compared with the flat control. Conclusion: The significant changes in the expression profile of anti-inflammatory genes could potentiate the therapeutic effect of BM-MSCs, encouraging the possible clinical translation for the treatment of pediatric congenital and acquired pulmonary disorders, including post-COVID lung manifestations. Lay Summary: Regenerative medicine is the research field integrating medicine, biology, and biomedical engineering. In this context, stem cells, which are a fundamental cell source able to regenerate tissues and restore damage in the body, are the key component for a regenerative therapeutic approach. When expanded outside the body, stem cells tend to differentiate spontaneously and lose regenerative potential due to external stimuli. For this reason, we exploit the scaffold named Nichoid, which mimics the in vivo cell niche architecture. In this scaffold, mesenchymal stem cells “feel at home” due to the three-dimensional mechanical stimuli, and our findings could be considered as an innovative culture system for the in vitro expansion of stem cells for clinical translation. Future Perspective: The increasing demand of safe and effective cell therapies projects our findings toward the possibility of improving cell therapies based on the use of BM-MSCs, particularly for their clinical translation in lung diseases. Graphical Abstract:

Published
2023
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4. Production of an induced pluripotent stem cell line CSSi018-A (14192) from a patient with hypomyelinating leukodystrophy 7 (HLD7) carrying biallelic variants of POLR3A (c.1802 T > A; c.4072G > A).

Author

Casamassa, Alessia, Rotundo, Giovannina, Ceresoni, Chiara, Turco, Elisa Maria, Torrente, Isabella, Candido, Ornella, Nicita, Francesco, Tonduti, Davide, Bertini, Enrico, Marano, Massimo, Ferrari, Daniela, Cereda, Cristina, Pennuto, Maria, Vescovi, Angelo Luigi, Carelli, Stephana, and Rosati, Jessica

Abstract

Hypomyelinating leukodystrophies (HLD) are a group of heterogeneous genetic disorders characterized by a deficit in myelin deposition during brain development. Specifically, 4H-Leukodystrophy is a recessive disease due to biallelic mutations in the POLR3A gene, which encodes one of the subunits forming the catalytic core of RNA polymerase III (PolIII). The disease also presents non-neurological signs such as hypodontia and hypogonadotropic hypogonadism. Here, we report the generation of a human induced pluripotent stem cell (hiPSC) line from fibroblasts of the first identified carrier of the biallelic POLR3A variants c.1802 T > A and c.4072G > A. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Role of epigenetics and alterations in RNAmetabolism in leukodystrophies

Author

Rey, Federica, Esposito, Letizia, Maghraby, Erika, Mauri, Alessia, Berardo, Clarissa, Bonaventura, Eleonora, Tonduti, Davide, Carelli, Stephana, and Cereda, Cristina

Abstract

Leukodystrophies are a class of rare heterogeneous disorders which affect the white matter of the brain, ultimately leading to a disruption in brain development and a damaging effect on cognitive, motor and social‐communicative development. These disorders present a great clinical heterogeneity, along with a phenotypic overlap and this could be partially due to contributions from environmental stimuli. It is in this context that there is a great need to investigate what other factors may contribute to both disease insurgence and phenotypical heterogeneity, and novel evidence are raising the attention toward the study of epigenetics and transcription mechanisms that can influence the disease phenotype beyond genetics. Modulation in the epigenetics machinery including histone modifications, DNA methylation and non‐coding RNAs dysregulation, could be crucial players in the development of these disorders, and moreover an aberrant RNA maturation process has been linked to leukodystrophies. Here, we provide an overview of these mechanisms hoping to supply a closer step toward the analysis of leukodystrophies not only as genetically determined but also with an added level of complexity where epigenetic dysregulation is of key relevance. This article is categorized under:Regulatory RNAs/RNAi/Riboswitches > Regulatory RNARNA in Disease and Development > RNA in DiseaseRNA in Disease and Development > RNA in Development Leukodystrophies are rare brain disorders affecting white matter, with a clinical diversity still to be explained. Beyond genetics, epigenetic factors like histone modifications, DNA methylation, and non‐coding RNA dysregulation, as well as aberrant RNA maturation, are emerging as crucial contributors to these disorders. Created with Biorender.com

Published
2024
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6. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Author

van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, Andre G., Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, de Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., and Veldink, Jan H.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

Published
2021
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7. Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Author

Johnson, Janel O., Chia, Ruth, Miller, Danny E., Li, Rachel, Kumaran, Ravindran, Abramzon, Yevgeniya, Alahmady, Nada, Renton, Alan E., Topp, Simon D., Gibbs, J. Raphael, Cookson, Mark R., Sabir, Marya S., Dalgard, Clifton L., Troakes, Claire, Jones, Ashley R., Shatunov, Aleksey, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Ticozzi, Nicola, Silani, Vincenzo, Gellera, Cinzia, Blair, Ian P., Dobson-Stone, Carol, Kwok, John B., Bonkowski, Emily S., Palvadeau, Robin, Tienari, Pentti J., Morrison, Karen E., Shaw, Pamela J., Al-Chalabi, Ammar, Brown, Robert H., Calvo, Andrea, Mora, Gabriele, Al-Saif, Hind, Gotkine, Marc, Leigh, Fawn, Chang, Irene J., Perlman, Seth J., Glass, Ian, Scott, Anna I., Shaw, Christopher E., Basak, A. Nazli, Landers, John E., Chiò, Adriano, Crawford, Thomas O., Smith, Bradley N., Traynor, Bryan J., Smith, Bradley N., Ticozzi, Nicola, Fallini, Claudia, Gkazi, Athina Soragia, Topp, Simon D., Scotter, Emma L., Kenna, Kevin P., Keagle, Pamela, Tiloca, Cinzia, Vance, Caroline, Troakes, Claire, Colombrita, Claudia, King, Andrew, Pensato, Viviana, Castellotti, Barbara, Baas, Frank, ten Asbroek, Anneloor L. M. A., McKenna-Yasek, Diane, McLaughlin, Russell L., Polak, Meraida, Asress, Seneshaw, Esteban-Pérez, Jesús, Stevic, Zorica, D’Alfonso, Sandra, Mazzini, Letizia, Comi, Giacomo P., Del Bo, Roberto, Ceroni, Mauro, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, van Rheenen, Wouter, Rademakers, Rosa, van Blitterswijk, Marka, Lauria, Giuseppe, Duga, Stefano, Corti, Stefania, Cereda, Cristina, Corrado, Lucia, Sorarù, Gianni, Williams, Kelly L., Nicholson, Garth A., Blair, Ian P., Leblond-Manry, Claire, Rouleau, Guy A., Hardiman, Orla, Morrison, Karen E., Veldink, Jan H., van den Berg, Leonard H., Al-Chalabi, Ammar, Pall, Hardev, Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Taroni, Franco, García-Redondo, Alberto, Wu, Zheyang, Glass, Jonathan D., Gellera, Cinzia, Ratti, Antonia, Brown, Robert H., Silani, Vincenzo, Shaw, Christopher E., Landers, John E., Dalgard, Clifton L., Adeleye, Adelani, Soltis, Anthony R., Alba, Camille, Viollet, Coralie, Bacikova, Dagmar, Hupalo, Daniel N., Sukumar, Gauthaman, Pollard, Harvey B., Wilkerson, Matthew D., Martinez, Elisa McGrath, Abramzon, Yevgeniya, Ahmed, Sarah, Arepalli, Sampath, Baloh, Robert H., Bowser, Robert, Brady, Christopher B., Brice, Alexis, Broach, James, Campbell, Roy H., Camu, William, Chia, Ruth, Cooper-Knock, John, Ding, Jinhui, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Eicher, John D., England, Bryce K., Faghri, Faraz, Feldman, Eva, Floeter, Mary Kay, Fratta, Pietro, Geiger, Joshua T., Gerhard, Glenn, Gibbs, J. Raphael, Gibson, Summer B., Glass, Jonathan D., Hardy, John, Harms, Matthew B., Heiman-Patterson, Terry D., Hernandez, Dena G., Jansson, Lilja, Kirby, Janine, Kowall, Neil W., Laaksovirta, Hannu, Landeck, Natalie, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J. L., Maragakis, Nicholas J., Mora, Gabriele, Mouzat, Kevin, Murphy, Natalie A., Myllykangas, Liisa, Nalls, Mike A., Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pickering-Brown, Stuart, Pioro, Erik P., Pletnikova, Olga, Pliner, Hannah A., Pulst, Stefan M., Ravits, John M., Renton, Alan E., Rivera, Alberto, Robberecht, Wim, Rogaeva, Ekaterina, Rollinson, Sara, Rothstein, Jeffrey D., Scholz, Sonja W., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Singleton, Andrew B., Smith, Nathan, Stone, David J., Tienari, Pentti J., Troncoso, Juan C., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Landers, John E., Chiò, Adriano, Traynor, Bryan J., Angelocola, Stefania M., Ausiello, Francesco P., Barberis, Marco, Bartolomei, Ilaria, Battistini, Stefania, Bersano, Enrica, Bisogni, Giulia, Borghero, Giuseppe, Brunetti, Maura, Cabona, Corrado, Calvo, Andrea, Canale, Fabrizio, Canosa, Antonio, Cantisani, Teresa A., Capasso, Margherita, Caponnetto, Claudia, Cardinali, Patrizio, Carrera, Paola, Casale, Federico, Chiò, Adriano, Colletti, Tiziana, Conforti, Francesca L., Conte, Amelia, Conti, Elisa, Corbo, Massimo, Cuccu, Stefania, Dalla Bella, Eleonora, D’Errico, Eustachio, DeMarco, Giovanni, Dubbioso, Raffaele, Ferrarese, Carlo, Ferraro, Pilar M., Filippi, Massimo, Fini, Nicola, Floris, Gianluca, Fuda, Giuseppe, Gallone, Salvatore, Gianferrari, Giulia, Giannini, Fabio, Grassano, Maurizio, Greco, Lucia, Iazzolino, Barbara, Introna, Alessandro, La Bella, Vincenzo, Lattante, Serena, Lauria, Giuseppe, Liguori, Rocco, Logroscino, Giancarlo, Logullo, Francesco O., Lunetta, Christian, Mandich, Paola, Mandrioli, Jessica, Manera, Umberto, Manganelli, Fiore, Marangi, Giuseppe, Marinou, Kalliopi, Marrosu, Maria Giovanna, Martinelli, Ilaria, Messina, Sonia, Moglia, Cristina, Mora, Gabriele, Mosca, Lorena, Murru, Maria R., Origone, Paola, Passaniti, Carla, Petrelli, Cristina, Petrucci, Antonio, Pozzi, Susanna, Pugliatti, Maura, Quattrini, Angelo, Ricci, Claudia, Riolo, Giulia, Riva, Nilo, Russo, Massimo, Sabatelli, Mario, Salamone, Paolina, Salivetto, Marco, Salvi, Fabrizio, Santarelli, Marialuisa, Sbaiz, Luca, Sideri, Riccardo, Simone, Isabella, Simonini, Cecilia, Spataro, Rossella, Tanel, Raffaella, Tedeschi, Gioacchino, Ticca, Anna, Torriello, Antonella, Tranquilli, Stefania, Tremolizzo, Lucio, Trojsi, Francesca, Vasta, Rosario, Vacchiano, Veria, Vita, Giuseppe, Volanti, Paolo, Zollino, Marcella, and Zucchi, Elisabetta

Abstract

IMPORTANCE: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. OBJECTIVE: To identify the genetic variants associated with juvenile ALS. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. MAIN OUTCOMES AND MEASURES: De novo variants present only in the index case and not in unaffected family members. RESULTS: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. CONCLUSIONS AND RELEVANCE: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Published
2021
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8. Phenotypic spectrum of short-chain enoyl-Coa hydratase-1 (ECHS1) deficiency.

Author

Masnada, Silvia, Parazzini, Cecilia, Bini, Paolo, Barbarini, Mario, Alberti, Luisella, Valente, Marialuisa, Chiapparini, Luisa, De Silvestri, Annalisa, Doneda, Chiara, Iascone, Maria, Saielli, Laura Assunta, Cereda, Cristina, Veggiotti, Pierangelo, Corbetta, Carlo, and Tonduti, Davide

Subjects
BASAL ganglia, DEVELOPMENTAL delay, DISEASE progression, DEGENERATION (Pathology)
Abstract

ECHS1 encodes for short-chain enoyl-CoA hydratase, a key component in b-oxidation. This enzyme is also involved in the isoleucine and valine catabolic pathways. The literature contains reports of scattered cases of ECHS1 mutation, which show a wide clinical spectrum of presentation. Despite that the clinical spectrum of the disease has not been defined so far due to the absence of previous systematic reviews and descriptions of large series of patients. We performed a systematic literature review of so far reported ECHS1 mutated patients and we reported two additional cases. We pointed out clinical and neuroradiological features of all patients. 45 patients were included in the analysis. Based on clinical and neuroradiological feature we were able to distinguish four main phenotypes of ECHS1deficiency: a severe neonatal presentation with a rapid and fatal course and significant white matter abnormalities; a severe infantile variant with slower neurological deterioration, developmental delay, pyramidal and extrapyramidal signs, optic atrophy, feeding difficulties, and degeneration of the deep gray nuclei; a slowly progressive infantile form, qualitatively similar to the previous phenotype, but less severe with mainly basal ganglia involvement; and a final phenotype, present in only few cases, characterized by paroxysmal exercise-induced dystonic attacks, normal neurological examination between these episodes, and isolated pallidal degeneration on MRI. ECHS1 mutations cause metabolic encephalopathy with a wide range of clinical presentations that can be grouped into four main phenotypes, each with a distinct profile in terms of severity on clinical presentation, disease course and MRI involvement. • ECHS1 mutations cause a metabolic encephalopathy with a wide range of clinical presentations. • Our study, on the basis of clinical and neuroradiological features, distinguish four main forms of ECHS1 deficiency. • The differences in phenotypes predict differences in clinical outcomes. [ABSTRACT FROM AUTHOR]

Published
2020
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9. cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

Author

Uggenti, Carolina, Lepelley, Alice, Depp, Marine, Badrock, Andrew P., Rodero, Mathieu P., El-Daher, Marie-Thérèse, Rice, Gillian I., Dhir, Somdutta, Wheeler, Ann P., Dhir, Ashish, Albawardi, Waad, Frémond, Marie-Louise, Seabra, Luis, Doig, Jennifer, Blair, Natalie, Martin-Niclos, Maria José, Della Mina, Erika, Rubio-Roldán, Alejandro, García-Pérez, Jose L., Sproul, Duncan, Rehwinkel, Jan, Hertzog, Jonny, Boland-Auge, Anne, Olaso, Robert, Deleuze, Jean-François, Baruteau, Julien, Brochard, Karine, Buckley, Jonathan, Cavallera, Vanessa, Cereda, Cristina, De Waele, Liesbeth M. H., Dobbie, Angus, Doummar, Diane, Elmslie, Frances, Koch-Hogrebe, Margarete, Kumar, Ram, Lamb, Kate, Livingston, John H., Majumdar, Anirban, Lorenço, Charles Marques, Orcesi, Simona, Peudenier, Sylviane, Rostasy, Kevin, Salmon, Caroline A., Scott, Christiaan, Tonduti, Davide, Touati, Guy, Valente, Marialuisa, van der Linden, Hélio, Van Esch, Hilde, Vermelle, Marie, Webb, Kate, Jackson, Andrew P., Reijns, Martin A. M., Gilbert, Nick, and Crow, Yanick J.

Abstract

Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi–Goutières syndrome, we identified biallelic mutations in LSM11and RNU7-1, which encode components of the replication-dependent histone pre-mRNA–processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS–stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.

Published
2020
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10. HuR interacts with lincBRN1a and lincBRN1b during neuronal stem cells differentiation

Author

Carelli, Stephana, Giallongo, Toniella, Rey, Federica, Latorre, Elisa, Bordoni, Matteo, Mazzucchelli, Serena, Gorio, Maria Carlotta, Pansarasa, Orietta, Provenzani, Alessandro, Cereda, Cristina, and Di Giulio, Anna Maria

Abstract

ABSTRACTLncRNAs play crucial roles in cellular processes and their regulatory effects in the adult brain and neural stem cells (NSCs) remain to be entirely characterized. We report that 10 lncRNAs (LincENC1, FABL, lincp21, HAUNT, PERIL, lincBRN1a, lincBRN1b, HOTTIP, TUG1 and FENDRR) are expressed during murine NSCs differentiation and interact with the RNA-binding protein ELAVL1/HuR. Furthermore, we characterize the function of two of the deregulated lncRNAs, lincBRN1a and lincBRN1b, during NSCs’ differentiation. Their inhibition leads to the induction of differentiation, with a concomitant decrease in stemness and an increase in neuronal markers, indicating that they exert key functions in neuronal cells differentiation. Furthermore, we describe here that HuR regulates their half-life, suggesting their synergic role in the differentiation process. We also identify six human homologs (PANTR1, TUG1, HOTTIP, TP53COR, ELDRR and FENDRR) of the mentioned 10 lncRNAs and we report their deregulation during human iPSCs differentiation into neurons. In conclusion, our results strongly indicate a key synergic role for lncRNAs and HuR in neuronal stem cells fate.

Published
2019
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11. Frailty as a risk factor for incident dementia and cognitive decline: Data from the longitudinal InveCe.Ab study: Neuropsychiatry and behavioral neurology/Dementia.

Author

Davin, Annalisa, Cereda, Cristina, Ardemagni, Deborah, Mimmi, Maria Chiara, Abbondanza, Simona, Vaccaro, Roberta, Poloni, Tino Emanuele, Medici, Valentina, Colombo, Mauro, and Guaita, Antonio

Abstract

Background: Frailty is a frequent and potentially reversible age‐related syndrome. Current evidence supports the associations between Frailty, cognitive impairment and dementia. The aim of the study is to estimate the predictive role of Frailty syndrome in incident dementia and cognitive impairment, as well as the modulation of genetic‐psycho‐social factors, such as APOEɛ4 polymorphism and loneliness in a non‐demented Italian cohort of elderly individuals. Method: Data are from a cohort of 1,321 persons aged 70‐74 years old, living in Abbiategrasso (Milan, Itay): the InveCe.Ab study (Guaita et al. 2013; clinical trials.gov NCT01345110). The sample took place in 2009 with follow‐ups in 2012 and 2014. Frailty was measured by Frailty Index (FI). The FI was then separated into Frail (FI>0.25), pre‐Frail (FI = 0.08‐0.25) and non‐Frail (FI < 0.08) groups. Dementia was defined using the DSM‐IV‐TR. Global cognition was assessed by the Mini Mental State Examination (MMSE), Comorbidity by Cumulative Illness Rating Scale (CIRS). Result: Frailty was associated with cumulative incidence of dementia (p<0.001), MMSE score at baseline (p<0.001), difference in MMSE score between 2009 and 2014 (p 0.005), CIRS (p<0.001).After four follow‐up years, 4.6% developed Dementia. In the longitudinal regression models adjusted for age, gender, level of education and loneliness, APOEɛ4 carrier status, Frailty was associated with incident dementia (OR=7.75,95% CI 3.26‐18.41), with higher risk of dementia for frail men compared to women (OR=13.79, 95% CI 4.11–46.21; OR= 4.63, 95% CI 1.32‐16.26, respectively). In linear regression models, adjusted for the same variables, Frailty also showed a significant association with the decrease of MMSE score in follow‐up only in males (male: β ‐0.131,95% CI ‐7.16 – ‐0.15; females: β‐0.085, 95% CI ‐5.60 – 0.19). Other covariates, such as loneliness, were independently associated with the outcomes. However, the interaction term for loneliness and frailty was not significant in predicting incident dementia. Conclusion: in our large population sample, Frailty is associated with cognitive impairment and cognitive decline. These results suggest that Frailty syndrome, especially if accompanied by other genetic‐psycho‐social characteristics such as loneliness, could be considered by clinicians as a red flag for early detection of cognitive disorders. [ABSTRACT FROM AUTHOR]

Published
2020
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12. Frailty as a risk factor for incident dementia and cognitive decline: Data from the longitudinal InveCe.Ab study: Neuropsychiatry and behavioral neurology/Dementia.

Author

Davin, Annalisa, Cereda, Cristina, Ardemagni, Deborah, Mimmi, Maria Chiara, Abbondanza, Simona, Vaccaro, Roberta, Poloni, Tino Emanuele, Medici, Valentina, Colombo, Mauro, and Guaita, Antonio

Abstract

Background: Frailty is a frequent and potentially reversible age‐related syndrome. Current evidence supports the associations between Frailty, cognitive impairment and dementia. The aim of the study is to estimate the predictive role of Frailty syndrome in incident dementia and cognitive impairment, as well as the modulation of genetic‐psycho‐social factors, such as APOEɛ4 polymorphism and loneliness in a non‐demented Italian cohort of elderly individuals. Method: Data are from a cohort of 1,321 persons aged 70‐74 years old, living in Abbiategrasso (Milan, Itay): the InveCe.Ab study (Guaita et al. 2013; clinical trials.gov NCT01345110). The sample took place in 2009 with follow‐ups in 2012 and 2014. Frailty was measured by Frailty Index (FI). The FI was then separated into Frail (FI>0.25), pre‐Frail (FI = 0.08‐0.25) and non‐Frail (FI < 0.08) groups. Dementia was defined using the DSM‐IV‐TR. Global cognition was assessed by the Mini Mental State Examination (MMSE), Comorbidity by Cumulative Illness Rating Scale (CIRS). Result: Frailty was associated with cumulative incidence of dementia (p<0.001), MMSE score at baseline (p<0.001), difference in MMSE score between 2009 and 2014 (p 0.005), CIRS (p<0.001).After four follow‐up years, 4.6% developed Dementia. In the longitudinal regression models adjusted for age, gender, level of education and loneliness, APOEɛ4 carrier status, Frailty was associated with incident dementia (OR=7.75,95% CI 3.26‐18.41), with higher risk of dementia for frail men compared to women (OR=13.79, 95% CI 4.11–46.21; OR= 4.63, 95% CI 1.32‐16.26, respectively). In linear regression models, adjusted for the same variables, Frailty also showed a significant association with the decrease of MMSE score in follow‐up only in males (male: β ‐0.131,95% CI ‐7.16 – ‐0.15; females: β‐0.085, 95% CI ‐5.60 – 0.19). Other covariates, such as loneliness, were independently associated with the outcomes. However, the interaction term for loneliness and frailty was not significant in predicting incident dementia. Conclusion: in our large population sample, Frailty is associated with cognitive impairment and cognitive decline. These results suggest that Frailty syndrome, especially if accompanied by other genetic‐psycho‐social characteristics such as loneliness, could be considered by clinicians as a red flag for early detection of cognitive disorders. [ABSTRACT FROM AUTHOR]

Published
2020
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13. A Novel Nonsense Angiogenin Mutation is Associated With Alzheimer Disease.

Author

Gagliardi, Stella, Davin, Annalisa, Bini, Paola, Sinforiani, Elena, Poloni, Tino E., Polito, Letizia, Rivoiro, Chiara, Binetti, Giuliano, Paterlini, Anna, Benussi, Luisa, Ghidoni, Roberta, Vanacore, Nicola, and Cereda, Cristina

Abstract

Highlights from the article: Mutations in the coding region of ANG have been detected in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD)[5] but no mutation has been described in AD. We screened a large cohort of Italian AD patients and healthy controls to identify mutations in the I ANG i gene. This new mutation has been found in 2 AD patients (0.20% the whole AD cohort): The first patient (patient 1) is the proband of pedigree FAM84 (Fig. 1B). We found a novel a nonsense mutation in the I ANG i gene in heterozygosis in position g.2162012 causing the change of a lysine to a Stop codon (K73X) in 2 AD patients (0.20%).

Published
2019
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14. The absence that makes the difference: choroidal abnormalities in Legius syndrome

Author

Tucci, Arianna, Saletti, Veronica, Menni, Francesca, Cesaretti, Claudia, Scuvera, Giulietta, Esposito, Silvia, Melloni, Giulia, Esposito, Susanna, Milani, Donatella, Cereda, Cristina, Cigada, Mario, Tresoldi, Laura, Viola, Francesco, and Natacci, Federica

Abstract

Neurofibromatosis type 1 (NF1) is an hereditary disorder characterized by abnormal proliferation of multiple tissues of neural crest origin, and presents mainly with multiple café-au-lait macules, axillary freckling and neurofibromas. Choroidal involvement in NF1 patients has been studied, thanks to the development of non-invasive tools such as infrared monochromatic light during fundus examination, which showed bright patchy lesions consistent with choroidal nodules. Choroidal abnormalities identified with near-infrared reflectance have reported with a frequency of up to 100% in NF1, and have been recently been proposed as a novel diagnostic criterion for NF1. Legius syndrome can be clinically indistinguishable from NF1 and results in a small percentage of individuals being misdiagnosed. We investigated the presence of choroidal abnormalities in Legius syndrome to determine their specificity to NF1 and their potential usefulness as a novel diagnostic criterion for NF1. We examined the fundus of 16 eyes by confocal scanning laser ophthalmoscopy with infrared monochromatic light in eight patients with molecularly confirmed Legius syndrome. No abnormalities were observed, confirming the diagnostic value of choroidal abnormalities for the diagnosis of NF1.

Published
2017
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15. Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry.

Author

Bersano, Anna, Markus, Hugh Stephen, Quaglini, Silvana, Arbustini, Eloisa, Lanfranconi, Silvia, Micieli, Giuseppe, Boncoraglio, Giorgio B., Taroni, Franco, Gellera, Cinzia, Baratta, Silvia, Penco, Silvana, Mosca, Lorena, Grasso, Maurizia, Carrera, Paola, Ferrari, Maurizio, Cereda, Cristina, Grieco, Gaetano, Corti, Stefania, Ronchi, Dario, and Bassi, Maria Teresa

Published
2016
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16. Hydrogen peroxide-mediated induction of SOD1 gene transcription is independent from Nrf2 in a cellular model of neurodegeneration.

Author

Dell'Orco, Michela, Milani, Pamela, Arrigoni, Laura, Pansarasa, Orietta, Sardone, Valentina, Maffioli, Elisa, Polveraccio, Francesca, Bordoni, Matteo, Diamanti, Luca, Ceroni, Mauro, Peverali, Fiorenzo A., Tedeschi, Gabriellla, and Cereda, Cristina

Abstract

Background It is still unclear whether oxidative stress (OS) is a disease consequence or is directly involved in the etiology of neurodegenerative disorders (NDs) onset and/or progression; however, many of these conditions are associated with increased levels of oxidation markers and damaged cell components. Previously we demonstrated the accumulation of reactive oxygen species (ROS) and increased SOD1 gene expression in H 2 O 2 -treated SH-SY5Y cells, recapitulating pathological features of Amyotrophic Lateral Sclerosis (ALS). Since we observed a post-transcriptional regulation of SOD1 gene in this cellular model, we investigated the transcriptional regulation of SOD1 mRNA under oxidative stress (OS). Results In response to H 2 O 2 treatment, PolII increased its association to SOD1 promoter. Electrophoretic mobility shift assays and mass spectrometry analyses on SOD1 promoter highlighted the formation of a transcriptional complex bound to the ARE sequences. Western Blotting experiments showed that in our in vitro model, H 2 O 2 exposure increases Nrf2 expression in the nuclear fraction while immunoprecipitation confirmed its phosphorylation and release from Keap1 inhibition. However, H 2 O 2 treatment did not modify Nrf2 binding on SOD1 promoter, which seems to be regulated by different transcription factors (TFs). Conclusions Although our data suggest that SOD1 is transcriptionally regulated in response to OS, Nrf2 does not appear to associate with SOD1 promoter in this cellular model of neurodegeneration. Our results open new perspectives in the comprehension of two key antioxidant pathways involved in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Published
2016
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18. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Author

van Rheenen, Wouter, Shatunov, Aleksey, Dekker, Annelot M, McLaughlin, Russell L, Diekstra, Frank P, Pulit, Sara L, van der Spek, Rick A A, Võsa, Urmo, de Jong, Simone, Robinson, Matthew R, Yang, Jian, Fogh, Isabella, van Doormaal, Perry TC, Tazelaar, Gijs H P, Koppers, Max, Blokhuis, Anna M, Sproviero, William, Jones, Ashley R, Kenna, Kevin P, van Eijk, Kristel R, Harschnitz, Oliver, Schellevis, Raymond D, Brands, William J, Medic, Jelena, Menelaou, Androniki, Vajda, Alice, Ticozzi, Nicola, Lin, Kuang, Rogelj, Boris, Vrabec, Katarina, Ravnik-Glavač, Metka, Koritnik, Blaž, Zidar, Janez, Leonardis, Lea, Grošelj, Leja Dolenc, Millecamps, Stéphanie, Salachas, François, Meininger, Vincent, de Carvalho, Mamede, Pinto, Susana, Mora, Jesus S, Rojas-García, Ricardo, Polak, Meraida, Chandran, Siddharthan, Colville, Shuna, Swingler, Robert, Morrison, Karen E, Shaw, Pamela J, Hardy, John, Orrell, Richard W, Pittman, Alan, Sidle, Katie, Fratta, Pietro, Malaspina, Andrea, Topp, Simon, Petri, Susanne, Abdulla, Susanne, Drepper, Carsten, Sendtner, Michael, Meyer, Thomas, Ophoff, Roel A, Staats, Kim A, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Van Deerlin, Vivianna M, Trojanowski, John Q, Elman, Lauren, McCluskey, Leo, Basak, A Nazli, Tunca, Ceren, Hamzeiy, Hamid, Parman, Yesim, Meitinger, Thomas, Lichtner, Peter, Radivojkov-Blagojevic, Milena, Andres, Christian R, Maurel, Cindy, Bensimon, Gilbert, Landwehrmeyer, Bernhard, Brice, Alexis, Payan, Christine A M, Saker-Delye, Safaa, Dürr, Alexandra, Wood, Nicholas W, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-François, Uitterlinden, Andre G, Rivadeneira, Fernando, Estrada, Karol, Hofman, Albert, Curtis, Charles, Blauw, Hylke M, van der Kooi, Anneke J, de Visser, Marianne, Goris, An, Weber, Markus, Shaw, Christopher E, Smith, Bradley N, Pansarasa, Orietta, Cereda, Cristina, Del Bo, Roberto, Comi, Giacomo P, D'Alfonso, Sandra, Bertolin, Cinzia, Sorarù, Gianni, Mazzini, Letizia, Pensato, Viviana, Gellera, Cinzia, Tiloca, Cinzia, Ratti, Antonia, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Arcuti, Simona, Capozzo, Rosa, Zecca, Chiara, Lunetta, Christian, Penco, Silvana, Riva, Nilo, Padovani, Alessandro, Filosto, Massimiliano, Muller, Bernard, Stuit, Robbert Jan, Blair, Ian, Zhang, Katharine, McCann, Emily P, Fifita, Jennifer A, Nicholson, Garth A, Rowe, Dominic B, Pamphlett, Roger, Kiernan, Matthew C, Grosskreutz, Julian, Witte, Otto W, Ringer, Thomas, Prell, Tino, Stubendorff, Beatrice, Kurth, Ingo, Hübner, Christian A, Leigh, P Nigel, Casale, Federico, Chio, Adriano, Beghi, Ettore, Pupillo, Elisabetta, Tortelli, Rosanna, Logroscino, Giancarlo, Powell, John, Ludolph, Albert C, Weishaupt, Jochen H, Robberecht, Wim, Van Damme, Philip, Franke, Lude, Pers, Tune H, Brown, Robert H, Glass, Jonathan D, Landers, John E, Hardiman, Orla, Andersen, Peter M, Corcia, Philippe, Vourc'h, Patrick, Silani, Vincenzo, Wray, Naomi R, Visscher, Peter M, de Bakker, Paul I W, van Es, Michael A, Pasterkamp, R Jeroen, Lewis, Cathryn M, Breen, Gerome, Al-Chalabi, Ammar, van den Berg, Leonard H, and Veldink, Jan H

Abstract

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Published
2016
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19. Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis

Author

Fogh, Isabella, Lin, Kuang, Tiloca, Cinzia, Rooney, James, Gellera, Cinzia, Diekstra, Frank P., Ratti, Antonia, Shatunov, Aleksey, van Es, Michael A., Proitsi, Petroula, Jones, Ashley, Sproviero, William, Chiò, Adriano, McLaughlin, Russell Lewis, Sorarù, Gianni, Corrado, Lucia, Stahl, Daniel, Del Bo, Roberto, Cereda, Cristina, Castellotti, Barbara, Glass, Jonathan D., Newhouse, Steven, Dobson, Richard, Smith, Bradley N., Topp, Simon, van Rheenen, Wouter, Meininger, Vincent, Melki, Judith, Morrison, Karen E., Shaw, Pamela J., Leigh, P. Nigel, Andersen, Peter M., Comi, Giacomo P., Ticozzi, Nicola, Mazzini, Letizia, D’Alfonso, Sandra, Traynor, Bryan J., Van Damme, Philip, Robberecht, Wim, Brown, Robert H., Landers, John E., Hardiman, Orla, Lewis, Cathryn M., van den Berg, Leonard H., Shaw, Christopher E., Veldink, Jan H., Silani, Vincenzo, Al-Chalabi, Ammar, and Powell, John

Abstract

IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. OBJECTIVE: To identify gene variants influencing survival in ALS. DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. MAIN OUTCOMES AND MEASURES: Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. RESULTS: Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10−9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10−8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 × 10−9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 × 10−8), corresponding to a 4-month reduction in survival compared with TT carriers. CONCLUSIONS AND RELEVANCE: This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.

Published
2016
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20. Clinical Pregenetic Screening for Stroke Monogenic Diseases

Author

Bersano, Anna, Markus, Hugh Stephen, Quaglini, Silvana, Arbustini, Eloisa, Lanfranconi, Silvia, Micieli, Giuseppe, Boncoraglio, Giorgio B., Taroni, Franco, Gellera, Cinzia, Baratta, Silvia, Penco, Silvana, Mosca, Lorena, Grasso, Maurizia, Carrera, Paola, Ferrari, Maurizio, Cereda, Cristina, Grieco, Gaetano, Corti, Stefania, Ronchi, Dario, Bassi, Maria Teresa, Obici, Laura, Parati, Eugenio A., Pezzini, Alessando, De Lodovici, Maria Luisa, Verrengia, Elena P., Bono, Giorgio, Mazucchelli, Francesca, Zarcone, Davide, Calloni, Maria Vittoria, Perrone, Patrizia, Bordo, Bianca Maria, Colombo, Antonio, Padovani, Alessandro, Cavallini, Anna, Beretta, Simone, Ferrarese, Carlo, Motto, Cristina, Agostoni, Elio, Molini, Graziella, Sasanelli, Francesco, Corato, Manuel, Marcheselli, Simona, Sessa, Maria, Comi, Giancarlo, Checcarelli, Nicoletta, Guidotti, Mario, Uccellini, Davide, Capitani, Erminio, Tancredi, Lucia, Arnaboldi, Marco, Incorvaia, Barbara, Tadeo, Carlo Sebastiano, Fusi, Laura, Grampa, Giampiero, Merlini, Giampaolo, Trobia, Nadia, Comi, Giacomo Pietro, Braga, Massimiliano, Vitali, Paolo, Baron, Pierluigi, Grond-Ginsbach, Caspar, and Candelise, Livia

Abstract

Supplemental Digital Content is available in the text.

Published
2016
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21. The Possible Involvement of HLA Class III Haplotype (RAGE, HSP70 and TNF Genes) in Alzheimer's Disease

Author

Boiocchi, Chiara, Maggioli, Elisa, Cristina Monti, Maria, Zorzetto, Michele, Sinforiani, Elena, Cereda, Cristina, Ricevuti, Giovanni, and Cuccia, Mariaclara

Abstract

In the central nervous system Hsp70s seems to have a protective role in repair and removal of cellular proteins damaged by stress conditions. A protective role of Hsp70 was also shown in Alzheimer Disease. The HSP70-1 +190 G/C polymorphism is located in the gene 5’UTR region and it is implicated in alteration of the transcription binding factor; HSP70-2 +1267 A/G causes a silent mutation in the coding region and it seems to influence the mechanism of mRNA translation; HSP70-hom +2437 A/G causes a substitution Met → The (M493T) in the coding region and it seems to influence the bond with the substrate and therefore on the chaperone activity of hsp70. The aim of our study will be to investigate Alzheimer susceptibility to Hsp70 polymorphisms, taking into account our previous findings on HLA class III region, and to hypothesize a role of HLA class III haplotype configuration based on the variants of three genes: RAGE, HSP70 and TNF. We studied these polymorphisms with PCR-RFLP and PCR-TSP. We investigated 173 AD patients and 211 control subjects. Our results have shown a statistically significant decrease of the C allele frequency of the HSP70-1 +190 G/C polymorphism in AD patients vs controls (P value = 0,018), as well as the G allele of HSP70-2 +1267 G/A (p value = 0,02). We focalized our attention on haplotype reconstruction. We have observed a significant statistically decrease of GGT haplotype frequency (empirical p-value=0.0133 ); GAT haplotype was statistically significant increase in AD patients compared with control (empirical p-value=0.007). The total HLA class III haplotype are reconstructed. The causative haplotypes are the following ones: TTGATGGG ( p value =0,005; empirical p =0,0042); TTGATAGG (p value =0,45; empirical p =0,034). Patients with these haplotypes may show an earlier onset of the disease than patients with TTGGTGGG (p value=0,0138; empirical p =0,0102); TTCGTGGG (p value=0,021; empirical p =0,017); TTCGTGGA (p value =0,058; empirical p =0,043) haplotypes. The overall variation of the haplotypes formed by the RAGE and TNF and HSP70 variants influenced the presence of the AD phenotype (omnibus association LR test p-value 0.00185), HSP701 and HSP702 showed independent effect on AD risk after adjusting for the effect of the entire haplotype (conditional LR test p-value=0.0114 and p-value=0.0044 respectively). These data confirm the involvement of HLA class III in AD.

Published
2015

22. Novel CLN3 mutation causing autophagic vacuolar myopathy.

Author

Cortese, Andrea, Tucci, Arianna, Piccolo, Giovanni, Galimberti, Carlo A, Fratta, Pietro, Marchioni, Enrico, Grampa, Gianpiero, Cereda, Cristina, Grieco, Gaetano, Ricca, Ivana, Pittman, Alan, Ciscato, Patrizia, Napoli, Laura, Lucchini, Valeria, Ripolone, Michela, Violano, Raffaella, Fagiolari, Gigliola, Mole, Sara E, Hardy, John, and Moglia, Arrigo

Published
2014
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23. Novel CLN3 mutation causing autophagic vacuolar myopathy.

Author

Cortese, Andrea, Tucci, Arianna, Piccolo, Giovanni, Galimberti, Carlo A., Fratta, Pietro, Marchioni, Enrico, Grampa, Gianpiero, Cereda, Cristina, Grieco, Gaetano, Ricca, Ivana, Pittman, Alan, Ciscato, Patrizia, Napoli, Laura, Lucchini, Valeria, Ripolone, Michela, Violano, Raffaella, Fagiolari, Gigliola, Mole, Sara E., Hardy, John, and Moglia, Arrigo

Published
2014
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24. DNA and RNA deep sequencing and epigenetic characterization of two kindred cases affected by slow and fast decline dementia: Genetics/omics and systems biology.

Author

Palmieri, Ilaria, Gagliardi, Stella, Valente, Maria Luisa, Zucca, Susanna, Davin, Annalisa, Medici, Valentina, Poloni, Tino Emanuele, Guaita, Antonio, and Cereda, Cristina

Abstract

Background: Genetics, transcriptomic and epigenetics play an important interplay in influencing the clinical picture and the final diagnosis of patients affected by neurodegenerative diseases. Clinical diagnosis is often inaccurate compared to the neuropathological one, which remains the gold standard for neurodegenerative disease diagnosis so far. For this reason, it becomes necessary to strengthener molecular efforts to sustain clinical diagnosis. Here, we present the molecular characterization of two kindred cases (mother and son) initially diagnosed as slow and fast dementia and, after post‐mortem neuropathological examination, classified as Alzheimer's Disease (AD) and Dementia with Lewy Body (DLB) respectively. Method: A customized panel of over 6000 genes associated to mendelian disorders and to inherited neurodegenerative diseases was sequenced by NGS (SureSelectQXT Target Enrichment, Agilent Technology) on peripheral blood DNA of the two patients. Total RNA from hippocampus, parietal lobe, substantia nigra and basal ganglia was extracted and RNA‐Seq analysis was run (SENSE Total RNA‐Seq, Lexogen). Differentially Expressed Genes (DEGs) were identified via R package DESeq2. Kegg pathway and Gene Ontology (GO) analyses for biological processes were made using enrichR. AlphaLisa analysis was performed on brain homogenates to investigate the dimethylation status of Histone 3 Lysine 9 (H3‐K9) and Histone 3 Lysine 4 (H3‐K4) and the acetylation status of H3‐K9. Result: Seven variants were found to be shared by patients (Table 1), while six variants were present only in the son and (Table 2). DEGs analysis revealed a dysregulation in the mother's hippocampus and in the son's substantia nigra, with a 10‐fold higher number of DEGs. GO analyses highlighted a deregulation in the epigenetic landscape. In particular, the substantia nigra of the son resulted hypomethylated and hyperacetylated respectively in the H3‐K9 residue, while the mother resulted globally hypermethylated in all the brain areas analysed at the H3‐K9 and H3‐K4 residues. Conclusion: We identified genetic factors that may explain the AD and the DBL phenotypes and DEGs in AD‐ and DBL‐specific brain areas involved in the epigenetic spectrum. Our investigation highlighted either the importance of DNA and RNA sequencing and the relevance to study the epigetic lanscape to support differential diagnoses of complex neurodegenerative pathologies. [ABSTRACT FROM AUTHOR]

Published
2020
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25. Brain donation for research: Features of the brain donors from the InveCe.Ab population‐based cohort.

Author

Davin, Annalisa, Rolandi, Elena, Poloni, Tino Emanuele, Medici, Valentina, Vaccaro, Roberta, Cirrincione, Alice, Cereda, Cristina, and Guaita, Antonio

Abstract

Background: Research on brain tissue is essential to understand the biological mechanisms underlying neurodegenerative diseases and brain aging processes.Brain donation for research is influenced by many factors both in clinical and non‐clinical samples. The aim of the present study is to explore the features associated with the decision to join the brain donation program of the Abbiategrasso Brain Bank (ABB) in the context of a population‐based study on brain aging. Method: The longitudinal cohort study InveCe.Ab enrolled participants aged 70‐75 years and residing in Abbiategrasso (MI). During the second follow‐up of the study (2014), the participants fill a questionnaire to investigate attitudes through brain donation for research purpose (N=1010). We compared socio‐cultural aspects and questionnaire responses between participants who adhere to brain donation (N=163; 16,1%) and those who refuse (N=847) using Student's t Test and chi‐squared test when appropriate. Variables showing significant differences in the group comparisons were included in a logistic regression model with brain donation status (yes/no) as the dependent variable. Result: The groups were comparable for age and sex, while ABB donors were significantly more educated (donors: 7,74, non‐donors: 6,70; p=0,000), more frequently prone to organ donation (donors: 93,4%; non‐donors: 64,3%, p=0,000) and to cremation (donors: 76,8%; non‐donors: 44,8%; p=0,000). Among those who were favorable for brain donation in the questionnaire, only 43,6% actually signed up for brain donation (p=0,000). Moreover, brain donation was associated with friends relationship satisfaction (donors: 96,5%; non‐donors: 91,4%; p=0,023) and better self‐reported health (donors: 83,3%; non‐donors: 73,4%; p=0,028), despite no difference between groups was found in the number of chronic disease (p=0,49). Finally, in the multivariable model, being prone to organ donation was the main factor associated with actual registration for brain donation. The availability for cremation remained significant only for males. Conclusion: Despite a positive attitude through brain donation in nearly half of the respondents, only a minority of older adults actually engage in a brain donation program. Being prone to organ donation was the main factor associated with brain donation subscription. The donors were more educated, with a positive attitude through their health and their relationships with friends. [ABSTRACT FROM AUTHOR]

Published
2021
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26. Novel CLN3mutation causing autophagic vacuolar myopathy

Author

Cortese, Andrea, Tucci, Arianna, Piccolo, Giovanni, Galimberti, Carlo A., Fratta, Pietro, Marchioni, Enrico, Grampa, Gianpiero, Cereda, Cristina, Grieco, Gaetano, Ricca, Ivana, Pittman, Alan, Ciscato, Patrizia, Napoli, Laura, Lucchini, Valeria, Ripolone, Michela, Violano, Raffaella, Fagiolari, Gigliola, Mole, Sara E., Hardy, John, Moglia, Arrigo, and Moggio, Maurizio

Abstract

To identify the genetic cause of a complex syndrome characterized by autophagic vacuolar myopathy (AVM), hypertrophic cardiomyopathy, pigmentary retinal degeneration, and epilepsy.

Published
2014
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27. The Human Leukocyte Antigen Class III Haplotype Approach: New Insight in Alzheimers Disease Inflammation Hypothesis

Author

Maggioli, Elisa, Boiocchi, Chiara, Zorzetto, Michele, Sinforiani, Elena, Cereda, Cristina, Ricevuti, Giovanni, and Cuccia, Mariaclara

Abstract

The Alzheimer’s disease “inflammation hypothesis” has emerged only recently, suggesting the risk of developing AD might be influenced by variants of genes encoding for inflammatory mediators. In order to investigate in this direction, genomic DNA from 194 Italian AD cases and 454 healthy controls matched by gender and ethnicity was analyzed for the Receptor for Advanced Glycation End products (RAGE, HLA class III-centromere portion) -374 and - 429 SNPs and for the Tumor Necrosis Factor-alpha (TNF-, HLA class III-telomere portion) -857, -308 and -238 SNPs by RFLP and Real Time PCR. Our data show statistically significant deviations between AD patients and healthy controls concerning RAGE -374 SNP genotype (TT: p=0.0084) and allele (T, A: p=0.0081) frequencies; TNF- -308 SNP AA genotype (p=0.0433) and TNF- -238 SNP genotype (GG: p=0.0138) and allele (G, A: p=0.0151) frequencies. Furthermore, significant differences between the study groups and regarding RAGE TC (p=0.05) and AC (p=0.009) haplotypes are present, while TNF- haplotype reconstruction point out a statistically significant difference between patients and controls regarding AGG haplotype (p=0.002). Finally, from the combination of the individually significant SNPs of the two genes (RAGE -374, TNF- -238 and -308) we performed an HLA class III haplotype reconstruction finding significant differences between AD subjects and controls regarding the TAG (p=0.019) and TGA (p=0.008) haplotypes. The implication of these haplotypes with the disease points to a possible involvement of entire HLA class III region in AD susceptibility.

Published
2013

28. Author Correction: Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Author

van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, Andre G., Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, de Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., and Veldink, Jan H.

Published
2022
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29. Habitual consumption of fruit, folic acid and cobalamin as risk/protection factors for the incidence of dementia: Data from the "InveCe.Ab" study: Prevention (nonpharmacological) / Nutrition.

Author

Davin, Annalisa, Ceretti, Arcangelo, Mimmi, Maria Chiara, Cereda, Cristina, and Guaita, Antonio

Abstract

Background: The role of diet as a modifiable factor that may affect the incidence of dementia is currently under investigation. The diet effect could be mediated by blood level of Folic Acid and Cobalamin, whose low levels are recognized as risk factors for dementia. The aim of this work is to evaluate the effects of habitual fruit intake, Cobalamin and Folic Acid on the cumulative incidence of dementia over a period of 4 years in elderly people free of basal dementia. Method: The subjects were 1321 people born between 1935‐39, enrolled in 2010 by the "InveCe.Ab" study (ClinicalTrials.gov ID: NCT01345110). The cohort was re‐evaluated in 2014 and the onset of dementia was ascertained. The association between fruit consumption and metabolic parameters with dementia at baseline was analyzed with t‐test for quantitative variables and with Pearson chi‐square for qualitative variables. The risk/protection effect of habitual fruit consumption and metabolic mediators on the onset of dementia after 4 years was evaluated by multiple logistic regression. Result: 988 subjects were included in the analysis, The new cases of dementia between 2010 and 2014 were 50. The high habitual fruit consumption was inversely associated with dementia incidence (p = 0.007) and also directly associated with higher levels of Folic Acid (p < 0.005). Women had higher levels of Folic Acid and Cobalamin (p < 0.001) and a tendency towards higher fruit consumption (p = 0.06). The logistic model using Folic Acid, Cobalamin, and sex as covariates, shows that the usual consumption of fruit reduces the 4‐year risk of developing dementia, (OR: 0.421; 95% CI: 0.213‐ 0.831) with a significant interaction between fruit consumption and Folate (OR: 0.771; 95% CI. 0.607‐0.980). Furthermore a higher level of Cobalamin results protective versus dementia. Conclusion: Our data show that in a population of 70‐75 years the cumulative incidence of dementia is significantly reduced by habitual fruit consumption independently of the plasma levels of Cobalamin. Folate could be the metabolic mediator of this protection. [ABSTRACT FROM AUTHOR]

Published
2020
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30. Raman spectroscopy reveals biochemical differences in plasma derived extracellular vesicles from sporadic Amyotrophic Lateral Sclerosis patients.

Author

Morasso, Carlo F., Sproviero, Daisy, Mimmi, Maria Chiara, Giannini, Marta, Gagliardi, Stella, Vanna, Renzo, Diamanti, Luca, Bernuzzi, Stefano, Piccotti, Francesca, Truffi, Marta, Pansarasa, Orietta, Corsi, Fabio, and Cereda, Cristina

Subjects
EXTRACELLULAR vesicles, AMYOTROPHIC lateral sclerosis, RAMAN spectroscopy, BLOOD plasma, NEURODEGENERATION
Abstract

Sporadic amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which there is no validated blood based biomarker. Extracellular vesicles (EVs) have the potential to solve this unmet clinical need. However, due to their heterogeneity and complex chemical composition, EVs are difficult to study. Raman spectroscopy (RS) is an optical method that seems particularly well suited to address this task. In fact, RS provides an overview of the biochemical composition of EVs quickly and virtually without any sample preparation. In this work, we studied by RS small extracellular vesicles (sEVs), large extracellular vesicles (lEVs) and blood plasma of sporadic ALS patients and of a matched cohort of healthy controls. The obtained results highlighted lEVs as a particularly promising biomarker for ALS. In fact, their Raman spectra show that sporadic ALS patients have a different lipid content and less intense bands relative to the aromatic amino acid phenylalanine. Plasma, large extracellular vesicles (lEVs) and small extracellular vesicles (sEVs) from patients affected by amyotrophic lateral sclerosis (ALS) and from a cohort of matched healthy controls were studied by means of Raman spectroscopy. The results obtained show that Raman spectroscopy is able to identify a specific fingerprint of each specimen and that the lEVs of ALS patients are characterized by a distinct biochemical composition. This study thus paves the road towards the use of lEVs as possible circulating biomarkers of ALS. Unlabelled Image • Raman detects differences between subtypes of extracellular vesicles (EVs). • Large EVs have a different lipid and protein content in patients with ALS. • Large EVs are a promising biomarker for the diagnosis of ALS. [ABSTRACT FROM AUTHOR]

Published
2020
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32. Generation of three isogenic induced Pluripotent Stem Cell lines (iPSCs) from fibroblasts of a patient with Aicardi Goutières Syndrome carrying a c.2471G>A dominant mutation in IFIH1 gene.

Author

Masneri, Stefania, Lanzi, Gaetana, Ferraro, Rosalba Monica, Barisani, Chiara, Piovani, Giovanna, Savio, Giulia, Cattalini, Marco, Galli, Jessica, Cereda, Cristina, Muzi-Falconi, Marco, Orcesi, Simona, Fazzi, Elisa, and Giliani, Silvia

Abstract

Aicardi-Goutières syndrome (AGS) is an early-onset monogenic encephalopathy characterized by intracranial calcification, leukodystrophy and cerebrospinal fluid lymphocytosis. To date, seven genes have been related to AGS. Among these, IFIH1 encodes for MDA5, a cytosolic double-stranded RNA receptor, and is responsible for AGS type 7. We generated three isogenic iPSC clones, using a Sendai virus-based vector, starting from fibroblasts of a patient carrying a dominant mutation in IFIH1. All lines were characterized for genomic integrity, genetic uniqueness, pluripotency, and differentiation capability. Our clones might offer a good model to investigate AGS7 pathophysiological mechanism and to discover new biomarkers for this condition treatment. [ABSTRACT FROM AUTHOR]

Published
2019
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33. Establishment of three iPSC lines from fibroblasts of a patient with Aicardi Goutières syndrome mutated in RNaseH2B.

Author

Ferraro, Rosalba Monica, Masneri, Stefania, Lanzi, Gaetana, Barisani, Chiara, Piovani, Giovanna, Savio, Giulia, Cattalini, Marco, Galli, Jessica, Cereda, Cristina, Muzi-Falconi, Marco, Orcesi, Simona, Fazzi, Elisa, and Giliani, Silvia

Abstract

We report the generation of three isogenic iPSC clones (UNIBSi007-A, UNIBSi007-B, and UNIBSi007-C) obtained from fibroblasts of a patient with Aicardi Goutières Syndrome (AGS) carrying a homozygous mutation in RNaseH2B. Cells were transduced using a Sendai virus based system, delivering the human OCT4, SOX2, c-MYC and KLF4 transcription factors. The resulting transgene-free iPSC lines retained the disease-causing DNA mutation, showed normal karyotype, expressed pluripotent markers and could differentiate in vitro toward cells of the three embryonic germ layers. [ABSTRACT FROM AUTHOR]

Published
2019
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34. Generation of three iPSC lines from fibroblasts of a patient with Aicardi Goutières Syndrome mutated in TREX1.

Author

Ferraro, Rosalba Monica, Lanzi, Gaetana, Masneri, Stefania, Barisani, Chiara, Piovani, Giovanna, Savio, Giulia, Cattalini, Marco, Galli, Jessica, Cereda, Cristina, Muzi-Falconi, Marco, Orcesi, Simona, Fazzi, Elisa, and Giliani, Silvia

Abstract

Fibroblasts from a patient with Aicardi Goutières Syndrome (AGS) carrying a compound heterozygous mutation in TREX1, were reprogrammed into induced pluripotent stem cells (iPSCs) to establish isogenic clonal stem cell lines: UNIBSi006-A, UNIBSi006-B, and UNIBSi006-C. Cells were transduced using the episomal Sendai viral vectors, containing human OCT4, SOX2, c-MYC and KLF4 transcription factors. The transgene-free iPSC lines showed normal karyotype, expressed pluripotent markers and displayed in vitro differentiation potential toward cells of the three embryonic germ layers. [ABSTRACT FROM AUTHOR]

Published
2019
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37. Sine causa tetraparesis

Author

Galli, Jessica, Gavazzi, Francesco, De Simone, Micaela, Giliani, Silvia, Garau, Jessica, Valente, Marialuisa, Vairo, Donatella, Cattalini, Marco, Mortilla, Marzia, Andreoli, (Laura, Badolato, Raffaele, Bianchi, Marika, Carabellese, Nice, Cereda, Cristina, Ferraro, Rosalba, Facchetti, Fabio, Fredi, Micaela, Gualdi, Giulio, Lorenzi, Luisa, Meini, Antonella, Orcesi, Simona, Tincani, Angela, Zanola, Alessandra, Rice, Gillian, Fazzi, Elisa, and Thachangattuthodi., Anish

Published
2018
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38. Lymphoblastoid cell lines as a model to understand amyotrophic lateral sclerosis disease mechanisms

Author

Pansarasa, Orietta, Bordoni, Matteo, Drufuca, Lorenzo, Diamanti, Luca, Sproviero, Daisy, Trotti, Rosa, Bernuzzi, Stefano, La Salvia, Sabrina, Gagliardi, Stella, Ceroni, Mauro, and Cereda, Cristina

Abstract

In the past, amyotrophic lateral sclerosis (ALS) has been considered a ‘neurocentric’ disease; however, new evidence suggests that it should instead be looked at from a ‘multisystemic’ or ‘non-neurocentric’ point of view. From 2006, we focused on the study of non-neural cells: ALS patients’ peripheral blood mononuclear cells (PMBCs) and lymphoblastoid cell lines (LCLs). Here, we characterize LCLs of sporadic ALS (sALS) and patients carrying SOD1, TARDBP and FUS mutations to identify an ALS biologically relevant molecular signature, and determine whether and how mutations differentially affect ALS-linked pathways. Although LCLs are different from motor neurons (MNs), in LCLs we found some features typical of degenerating MNs in ALS, i.e. protein aggregation and mitochondrial dysfunction. Moreover, different gene mutations have different effects on ALS cellular mechanisms. TARDBP and FUS mutations imbalance mitochondrial dynamism toward increased fusion, whereas sALS and SOD1 mutations mainly affect fission. With regards to protein aggregation and/or mislocalization, TARDBP and SOD1 mutations show the presence of aggregates, whereas FUS mutation does not induce protein aggregation and/or mislocalization. Finally, all LCLs, independently from mutation, are not able to work in a condition of excessive energy request, suggesting that mitochondria from ALS patients are characterized by a significant metabolic defect. Taken together, these data indicate that LCLs could be a valid cellular model in ALS research in the identification and study of specific pathological pathways.

Published
2018
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39. Correction: The absence that makes the difference: choroidal abnormalities in Legius syndrome

Author

Tucci, Arianna, Saletti, Veronica, Menni, Francesca, Cesaretti, Claudia, Scuvera, Giulietta, Esposito, Silvia, Melloni, Giulia, Esposito, Susanna, Milani, Donatella, Cereda, Cristina, Cigada, Mario, Tresoldi, Laura, Viola, Francesco, and Natacci, Federica

Abstract

Correction to: Journal of Human Genetics advance online publication 27 July 2017; 10.1038/jhg.2017.78

Published
2018
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