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51. ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry

Author

Borghero, G, Pugliatti, M, Marrosu, F, Marrosu, M, Murru, M, Floris, G, Cannas, A, Parish, L, Cau, T, Loi, D, Ticca, A, Traccis, S, Manera, U, Canosa, A, Moglia, C, Calvo, A, Barberis, M, Brunetti, M, Renton, A, Nalls, M, Traynor, B, Restagno, G, Chiò, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Capasso, M, Caponnetto, C, Mancardi, G, Mandich, P, Origone, P, Conforti, F, Mora, G, Marinou, K, Sideri, R, Lunetta, C, Penco, S, Mosca, L, Nilo, R, Pinter, G, Corbo, M, Volanti, P, Mandrioli, J, Fini, N, Georgoulopoulou, E, Tremolizzo, L, Monsurròad, M, Tedeschi, G, Cristillo, V, la Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Giannini, F, Battistini, S, Ricci, C, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Bertuzzo, D, Tanel, R, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Pirisi, A, Occhineri, P, Ortu, E, Logullo, FO, Conforti, FL, Pinter, GL, Monsurròad, MR, Borghero, G, Pugliatti, M, Marrosu, F, Marrosu, M, Murru, M, Floris, G, Cannas, A, Parish, L, Cau, T, Loi, D, Ticca, A, Traccis, S, Manera, U, Canosa, A, Moglia, C, Calvo, A, Barberis, M, Brunetti, M, Renton, A, Nalls, M, Traynor, B, Restagno, G, Chiò, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Capasso, M, Caponnetto, C, Mancardi, G, Mandich, P, Origone, P, Conforti, F, Mora, G, Marinou, K, Sideri, R, Lunetta, C, Penco, S, Mosca, L, Nilo, R, Pinter, G, Corbo, M, Volanti, P, Mandrioli, J, Fini, N, Georgoulopoulou, E, Tremolizzo, L, Monsurròad, M, Tedeschi, G, Cristillo, V, la Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Giannini, F, Battistini, S, Ricci, C, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Bertuzzo, D, Tanel, R, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Pirisi, A, Occhineri, P, Ortu, E, Logullo, FO, Conforti, FL, Pinter, GL, and Monsurròad, MR

Abstract

Intermediate-length CAG expansions (encoding 27-33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that ≥31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with ≥31 polyQ repeats had a spinal onset versus 73.3% of patients with <31 polyQ repeats. Patients with an increased number of polyQ repeats have a shorter survival than those with <31 repeats (1.2 vs. 4.2 years, p = 0.035). In this large series of ALS patients of Sardinian ancestry, we have found that ≥31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival.

Published
2015

52. Primary fibroblasts cultures reveal TDP-43 abnormalities in amyotrophic lateral sclerosis patients with and without SOD1 mutations

Author

Mirabella, Massimiliano, Zollino, Marcella, Conte, A, Del Grande, A, Marangi, Giuseppe, Lucchini, M, Mirabella, M, Romano, A, Piacentini, Roberto, Bisogni, G, Lattante, S, Luigetti, Marco, Rossini, Paolo Maria, Moncada, A., Sabatelli, M (ORCID:0000-0002-7783-114X), Zollino, M (ORCID:0000-0003-4871-9519), Marangi, G (ORCID:0000-0002-6898-8882), Piacentini, Roberto (ORCID:0000-0003-4215-1643), Luigetti, Marco (ORCID:0000-0001-7539-505X), Rossini, Paolo Maria (ORCID:0000-0003-2665-534X), Mirabella, Massimiliano, Zollino, Marcella, Conte, A, Del Grande, A, Marangi, Giuseppe, Lucchini, M, Mirabella, M, Romano, A, Piacentini, Roberto, Bisogni, G, Lattante, S, Luigetti, Marco, Rossini, Paolo Maria, Moncada, A., Sabatelli, M (ORCID:0000-0002-7783-114X), Zollino, M (ORCID:0000-0003-4871-9519), Marangi, G (ORCID:0000-0002-6898-8882), Piacentini, Roberto (ORCID:0000-0003-4215-1643), Luigetti, Marco (ORCID:0000-0001-7539-505X), and Rossini, Paolo Maria (ORCID:0000-0003-2665-534X)

Abstract

TAR DNA-binding protein 43 (TDP-43) is a major component of the pathologic inclusions observed in the motor neurons of amyotrophic lateral sclerosis (ALS) patients. We examined TDP-43 expression in primary fibroblasts cultures from 22 ALS patients, including cases with SOD1 (n = 4), TARDBP (n = 4), FUS (n = 2), and C9ORF72 (n = 3) mutations and 9 patients without genetic defect. By using a phosphorylation-independent antibody, 15 patients showed notable alterations of TDP-43 level in the nuclear or cytoplasmic compartments. In particular, a marked accumulation of TDP-43 was observed in the cytoplasm of all cases with C9ORF72 and TARDBP mutations, 1 patient with FUS mutation and 3 patients without genetic defect. Patients with SOD1 mutations revealed a significant reduction of TDP-43 in the nuclei without cytoplasmic mislocalization. These changes were associated with the presence of truncated and phosphorylated TDP-43 species. Our results show that fibroblasts recapitulate some of hallmark TDP-43 abnormalities observed in neuronal cells. The reduction of full-length TDP-43 level in mutant SOD1 cells indicates that at least some SOD1 mutations alter TDP-43 metabolism.

Published
2015

53. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

Author

Chiò, A1, Borghero, G, Restagno, G, Mora, G, Drepper, C, Traynor, Bj, Sendtner, M, Brunetti, M, Ossola, I, Calvo, A, Pugliatti, M, Sotgiu, Ma, Murru, Mr, Marrosu, Mg, Marrosu, F, Marinou, K, Mandrioli, J, Sola, P, Caponnetto, C, Mancardi, G, Mandich, P, La Bella, V, Spataro, R, Conte, A, Monsurrò, Mr, Tedeschi, G, Pisano, F, Bartolomei, I, Salvi, F, Lauria Pinter, G, Simone, I, Logroscino, G, Gambardella, A, Quattrone, A, Lunetta, C, Volanti, P, Zollino, M, Penco, S, Battistini, S, Renton, Ae, Majounie, E, Abramzon, Y, Conforti, Fl, Giannini, F, Corbo, M, Sabatelli, M, Moglia, C, Cammarosano, S, Fuda, G, Canosa, A, Gallo, S, Papetti, L, Luigetti, M, Lattante, S, Marangi, G, Colletti, T, Ricci, C, Origone, P, Floris, G, Cannas, A, Piras, V, Parish, Ld, Solinas, G, Ulgheri, L, Ticca, A, Izzo, F, Laiola, A, Trojsi, F., Chiò, A, Borghero, G, Restagno, G, Mora, G, Drepper, C, Traynor, Bj, Sendtner, M, Brunetti, M, Ossola, I, Calvo, A, Pugliatti, M, Sotgiu, Ma, Murru, Mr, Marrosu, Mg, Marrosu, F, Marinou, K, Mandrioli, J, Sola, P, Caponnetto, C, Mancardi, G, Mandich, P, La Bella, V, Spataro, R, Conte, A, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Pisano, F, Bartolomei, I, Salvi, F, Lauria Pinter, G, Simone, I, Logroscino, G, Gambardella, A, Quattrone, A, Lunetta, C, Volanti, P, Zollino, M, Penco, S, Battistini, S, the ITALSGEN consortium: Moglia, Cristina, Cammarosano, Stefania, Fuda, Giuseppe, Canosa, Antonio, Gallo, Sara, Papetti, Laura, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Colletti, Tiziana, Ricci, Claudia, Origone, Paola, Floris, Gianluca, Cannas, Antonino, Piras, Valeria, Parish, Leslie D, Solinas, Giuliana, Ulgheri, Lucia, Ticca, Anna, Izzo, Francesco, Laiola, Anna, Trojsi, Francesca, Renton, Ae, Majounie, E, Abramzon, Y, Conforti, Fl, Giannini, F, Corbo, M, Sabatelli, M., Chiò, A., Borghero, G., Restagno, G., Mora, G., Drepper, C., Traynor, B., Sendtner, M., Brunetti, M., Ossola, I., Calvo, A., Pugliatti, M., Sotgiu, M., Murru, M., Marrosu, G., Marrosu, F., Marinou, K., Mandrioli, J., Sola, P., Caponnetto, C., Mancardi, G., Mandich, P., LA BELLA, V., Spataro, R., Conte, A., Monsurrò, M., Tedeschi, G., Pisano, F., Bartolomei, I., Salvi, F., Lauria, G., Simone, I., Logroscino, G., Gambardella, A., Quattrone, A., Lunetta, C., Volanti, P., Zollino, M., Penco, S., Battistini, S., the ITALSGEN, C., Renton, A., Majounie, E., Abramzon, Y., Conforti, F., Giannini, F., and Corbo, M.

Subjects
Male, Parents, Pathology, phenotype-genotype correlation, Cohort Studies, 0302 clinical medicine, C9orf72, amyotrophic lateral sclerosi, genetics, Amyotrophic lateral sclerosis, Age of Onset, amyotrophic lateral sclerosis, familial als, C9Orf72, 0303 health sciences, Sex Characteristics, DNA Repeat Expansion, Adult, Age of Onset, Aged, Amyotrophic Lateral Sclerosis, genetics/pathology, Cohort Studies, DNA Repeat Expansion, DNA, genetics, Female, Humans, Italy, Male, Middle Aged, Mutation, genetics, Parents, Pedigree, Phenotype, Proteins, genetics, Sex Characteristics, Survival Analysis, Middle Aged, 3. Good health, Pedigree, Settore MED/26 - NEUROLOGIA, Phenotype, Italy, Settore MED/26 - Neurologia, Female, Frontotemporal dementia, Adult, medicine.medical_specialty, SOD1, Biology, TARDBP, 03 medical and health sciences, Internal medicine, medicine, Humans, 030304 developmental biology, Aged, amyotrophic lateral sclerosis, familial ALS, C9ORF72 gene, phenotype–genotype correlation, C9orf72 Protein, Amyotrophic Lateral Sclerosis, genetics/pathology, Proteins, Original Articles, DNA, medicine.disease, Survival Analysis, Settore BIO/18 - Genetica, familial ALS, C9ORF72 gene, Mutation, Neurology (clinical), Age of onset, Trinucleotide repeat expansion, familial al, 030217 neurology & neurosurgery
Abstract

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis–frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis–frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6–7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7–2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for 60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis. Keywords

Published
2012

56. The role of excitons' quasiequilibrium in the temperature dependence of the poly(9,9-dioctylfluorene) beta phase photoluminescence

Author

Anni, M, Caruso, ME, Lattante, S, and Cingolani, R

Subjects
2-DIMENSIONAL DISTRIBUTED-FEEDBACK, LIGHT-EMITTING-DIODES, SINGLE QUANTUM DOTS, POLYFLUORENE, CONJUGATED-POLYMER
Abstract

We investigated the temperature dependence of the poly(9,9-dioctylfluorene) beta phase photoluminescence (PL) spectra in spin coated thin films from tetrahydrofuran solutions. As the temperature increases from 18 to 300 K a continuous blueshift of the 0-0 PL peak of about 25 meV and an increase of the peak full width at half maximum (FWHM) of about 49 meV are observed. We show that the PL spectra temperature dependence is not due to a temperature dependent average conjugation length, as often assumed, but instead it can be quantitatively explained in the frame of a thermal quasiequilibrium model for excitons in an inhomogeneously broadened excited states distribution. We demonstrate that the emission blueshift and broadening are mainly due to the increase of the excitons' temperature with the sample one. This effect is partially compensated by an increasing efficiency of the exciton energy migration. The interplay between these two processes quantitatively explains the observed temperature dependence of the PL peak energy and of its FWHM. On the contrary we show that the PL spectra are almost independent of the absorption blueshift with temperature. (c) 2006 American Institute of Physics.

Published
2006

57. Optical gain in fluorenyl-thiophene co-oligomer thin films

Author

Lattante S., Anni M.b, Salerno M., Lagonigro L., Cingolani R., Gigli G., Destri S., W. Porzio, and M.C. Pasini

Subjects
POLYFLUORENE LASERS, AMPLIFIED SPONTANEOUS EMISSION, 2-DIMENSIONAL DISTRIBUTED-FEEDBACK, STIMULATED-EMISSION, LIGHT AMPLIFICATION
Abstract

We report on the emission properties of thin films of a fluorenyl-thiophene co-oligomer under strong optical excitation. A clear line narrowing is observed in the emission spectra as a function of the excitation density, due to a Stimulated Emission band attributed to Amplified Spontaneous Emission (ASE). The ASE threshold of about 150 lJ cm_2 is comparable with the best values reported for other oligomeric and/or co-oligomeric films or crystals. A maximum gain value of about 8 cm_1 is obtained for an excitation density of about 940 lJ cm_2. These results propose fluorene-thiophene co-oligomers as interesting materials for high performance optically pumped laser devices.

Published
2006

60. Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease

Author

Lattante, S, Conte, A, Zollino, M, Luigetti, M, Del Grande, A, Marangi, G, Romano, A, Marcaccio, A, Meleo, E, Bisogni, G, Rossini, Paolo Maria, Sabatelli, M., Rossini, Paolo Maria (ORCID:0000-0003-2665-534X), Lattante, S, Conte, A, Zollino, M, Luigetti, M, Del Grande, A, Marangi, G, Romano, A, Marcaccio, A, Meleo, E, Bisogni, G, Rossini, Paolo Maria, Sabatelli, M., and Rossini, Paolo Maria (ORCID:0000-0003-2665-534X)

Abstract

To quantify the overall contribution of mutations in the currently known amyotrophic lateral sclerosis (ALS) genes in a large cohort of sporadic patients and to make genotype-phenotype correlations.

Published
2012

63. Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis

Author

Sabatelli, M., primary, Eusebi, F., additional, Al-Chalabi, A., additional, Conte, A., additional, Madia, F., additional, Luigetti, M., additional, Mancuso, I., additional, Limatola, C., additional, Trettel, F., additional, Sobrero, F., additional, Di Angelantonio, S., additional, Grassi, F., additional, Di Castro, A., additional, Moriconi, C., additional, Fucile, S., additional, Lattante, S., additional, Marangi, G., additional, Murdolo, M., additional, Orteschi, D., additional, Del Grande, A., additional, Tonali, P., additional, Neri, G., additional, and Zollino, M., additional

Published
2009
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73. Excitation Density Dependence of Optical Oxygen Sensing in Poly(9,9-dioctylfluorene) Waveguides Showing Amplified Spontaneous Emission.

Author

Anni, M. and Lattante, S.

Subjects
*OXYGEN detectors, *POLYFLUORENES, *WAVEGUIDES, *PHOTON emission, *QUENCHING (Chemistry), *SENSITIVITY analysis
Abstract

Reversible oxygen induced emission quenching of both the Spontaneous Emission (SE) and the Amplified Spontaneous Emission (ASE) of poly(9,9-dioctylfluorene) waveguides is demonstrated. We showthat ASE shows a stronger quenching than SE, up to about 6.2 times, but also a stronger decrease when the excitation density increases. We conclude that the fast increase of the ASE decay rate is the main process in determining the ASE detection sensitivity, limiting the potentiality of sensitivity improvement of ASE with respect to SE. [ABSTRACT FROM AUTHOR]

Published
2014
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74. On the spatial inhomogeneity of charge generation and collection in inverted all polymer solar cells.

Author

Perulli, A., Lattante, S., Persano, A., Cola, A., Di Giulio, M., and Anni, M.

Subjects
*SOLAR cells, *PHOTOLUMINESCENCE, *QUANTUM efficiency, *HETEROJUNCTIONS, *ENERGY harvesting, *MATHEMATICAL models
Abstract

Simultaneous photoluminescence (PL) and external quantum efficiency (EQE) confocal mapping is used to investigate the correlation between the local PL and the EQE in a regioregular poly(3-exylthiophene):poly(9,9-dioctylfluorene-co-benzothiadiazole) inverted bulk heterojunction solar cell. We show that the charge generation and charge collection are strongly non-uniform on a length scale up to 100 µm. Our results evidence that organic solar cells optimization requires not only the control of the submicrometric active materials arrangement but also the control of the large scale device uniformity. [ABSTRACT FROM AUTHOR]

Published
2013
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76. Microscopic Investigation of the Excitons' Intermolecular Energy Migration in the Phase of Poly(9,9-dioctylfluorene) by Confocal Laser Spectroscopy

Author

Anni, M., E. Caruso, M., and Lattante, S.

Abstract

We investigated, by confocal laser spectroscopy, the role of the microscopic morphology on the fluorescence spectra of poly(9,9-dioctylfluorene) (PF8) thin films self-doped by the PF8 phase. We demonstrate the existence, on the micron scale, of different regions in the films, characterized by locally different fluorescence spectra. We show that the microscopic morphology irregularities lead to locally nonuniform -phase density resulting in the switching on or off of the intermolecular energy migration within the -phase excited-state distribution. This effect causes considerable local variation of the fluorescence spectra consisting of a progressive red shift (up to 26 meV) and a line width narrowing from about 70 (similar to the absorption one) down to 52 meV.

Published
2008
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77. Efficient stimulated emission due to bimolecular annihilation reduction in oligothiophene dioxide thin films.

Author

Lattante, S., Barbarella, G., Favaretto, L., Gigli, G., Cingolani, R., and Anni, M.

Subjects
*OPTICS, *THIN films, *MOLECULES, *INDUSTRIAL lasers, *LASER ablation, *PHYSICS
Abstract

We have studied the optical properties of a thienyl-S, S-dioxide oligothiophene under strong excitation. No stimulated emission is observed in neat films due to singlet-singlet bimolecular annihilation, with a bimolecular constant of A=(4.5±0.5)×10-11 cm3 s-1. On the contrary we show that strong stimulated emission is observed if the active molecule is blended to an inert polymer [poly(bisphenol A carbonate] (PC) even for a PC content as low as one PC molecule every 500 active molecules. We suggest that small PC quantities modify the film superamolecular packing, thus reducing the bimolecular recombination efficiency. These results are expected to be quite general and could allow a considerable extension of the number of molecules showing stimulated emission for organic laser applications. [ABSTRACT FROM AUTHOR]

Published
2006
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78. Pitt-Hopkins syndrome: dissecting the clinical and genetic heterogeneity of conditions in the phenotypic spectrum

Author

Marangi, G., Frangella, S., Ricciardi, S., Chiurazzi, P., Orteschi, D., Lattante, S., Pettinato, R., Martinez, F., Magnani, C., Pantaleoni, C., Perria, C., Scarano, G., Saletti, V., Bonanni, P., Vasco, G., Lo Rizzo, C., Volzone, A., Alfei, E., Faletra, F., Romano, S., Renieri, A., Giannotta, M., Minetti, C., Bruno, C., Piccione, M., Stanzial, F., Della Monica, M., Ardissone, A., Di Giacomo, M., Agatino Battaglia, Graziano, C., Garavelli, L., and Zollino, M.

79. The HFE p.HIS63ASP polymorphism modifies ALS outcome in patients with SOD1 mutations

Author

Chiò, A., Calvo, A., Mora, G., Brunetti, M., Barberis, M., Borghero, G., Caponnetto, C., Monsurrò, Mr, La Bella, V., Volanti, P., Simone, I., Salvi, F., Logullo, F., Nilo, R., Tremolizzo, L., Giannini, F., JESSICA MANDRIOLI, Tanel, R., Murru, Mr, Mandich, P., Conforti, Fl, Italsgen, Consortium, Sardinials, Consortium, Zollino, M., Lattante, S., Sabatelli, M., Tarlarini, C., Penco, S., Russo, M., Messina, S., Lunetta, C., Meininger, V., Clavelou, P., and Camu, W.

Subjects
HFE mutation, ALS

80. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, Als gene, Genome-wide association study, FAMILIAL ALS, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, 0302 clinical medicine, 80 and over, Psychology, Aetiology, Aged, 80 and over, 0303 health sciences, French ALS Consortium, Kinesin, KINESIN HEAVY-CHAIN, Cognitive Sciences, Human, Hereditary spastic paraplegia, Neuroscience(all), Single-nucleotide polymorphism, TARGETED DISRUPTION, Article, 03 medical and health sciences, Genetics, Humans, Amino Acid Sequence, Loss function, Aged, HEXANUCLEOTIDE REPEAT, Neuroscience (all), MUTATIONS, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, 1702 Cognitive Science, medicine.disease, ITALSGEN Consortium, Answer ALS Foundation, 030104 developmental biology, ALS Sequencing Consortium, Human medicine, 1109 Neurosciences, 030217 neurology & neurosurgery, 0301 basic medicine, [SDV]Life Sciences [q-bio], Kinesins, Neurodegenerative, Genetic analysis, Genome, AMYOTROPHIC-LATERAL-SCLEROSIS, 3124 Neurology and psychiatry, Cohort Studies, Pathogenesis, Loss of Function Mutation, Missense mutation, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, NYGC ALS Consortium, General Neuroscience, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, Middle Aged, Phenotype, Settore MED/26 - NEUROLOGIA, Neurological, Project MinE ALS Sequencing Consortium, Female, Adult, Biology, GENOTYPE IMPUTATION, Genome-Wide Association Study, Young Adult, NO, Rare Diseases, medicine, SLAGEN Consortium, Gene, 030304 developmental biology, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Neurology & Neurosurgery, Human Genome, Neurosciences, AXONAL-TRANSPORT, Brain Disorders, Family member, DNA-DAMAGE, MOTOR-NEURONS, 3111 Biomedicine, Cohort Studie, Genomic Translation for ALS Care (GTAC) Consortium, Amyotrophic Lateral Sclerosi
Abstract

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Published
2018
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81. Characterization of the p.L145F and p.S135N Mutations in SOD1: Impact on the Metabolism of Fibroblasts Derived from Amyotrophic Lateral Sclerosis Patients

Author

Elisa Perciballi, Federica Bovio, Jessica Rosati, Federica Arrigoni, Angela D’Anzi, Serena Lattante, Maurizio Gelati, Fabiola De Marchi, Ivan Lombardi, Giorgia Ruotolo, Matilde Forcella, Letizia Mazzini, Sandra D’Alfonso, Lucia Corrado, Mario Sabatelli, Amelia Conte, Luca De Gioia, Sabata Martino, Angelo Luigi Vescovi, Paola Fusi, Daniela Ferrari, Perciballi, E, Bovio, F, Rosati, J, Arrigoni, F, D'Anzi, A, Lattante, S, Gelati, M, De Marchi, F, Lombardi, I, Ruotolo, G, Forcella, M, Mazzini, L, D'Alfonso, S, Corrado, L, Sabatelli, M, Conte, A, De Gioia, L, Martino, S, Vescovi, A, Fusi, P, and Ferrari, D

Subjects
amyotrophic lateral sclerosis, energetic metabolism, SOD1 expression, Physiology, ALS, p.L144F, p.S134N, SOD1 mutations, seahorse, p.L145F, p.S135N, mitochondria, Clinical Biochemistry, Cell Biology, Settore MED/03 - GENETICA MEDICA, Biochemistry, SOD1 mutation, metabolic studies, amyotrophic lateral sclerosi, Molecular Biology
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of the upper and lower motor neurons (MNs). About 10% of patients have a family history (familial, fALS); however, most patients seem to develop the sporadic form of the disease (sALS). SOD1 (Cu/Zn superoxide dismutase-1) is the first studied gene among the ones related to ALS. Mutant SOD1 can adopt multiple misfolded conformation, lose the correct coordination of metal binding, decrease structural stability, and form aggregates. For all these reasons, it is complicated to characterize the conformational alterations of the ALS-associated mutant SOD1, and how they relate to toxicity. In this work, we performed a multilayered study on fibroblasts derived from two ALS patients, namely SOD1L145F and SOD1S135N, carrying the p.L145F and the p.S135N missense variants, respectively. The patients showed diverse symptoms and disease progression in accordance with our bioinformatic analysis, which predicted the different effects of the two mutations in terms of protein structure. Interestingly, both mutations had an effect on the fibroblast energy metabolisms. However, while the SOD1L145F fibroblasts still relied more on oxidative phosphorylation, the SOD1S135N fibroblasts showed a metabolic shift toward glycolysis. Our study suggests that SOD1 mutations might lead to alterations in the energy metabolism.

Published
2022

82. Generation of an induced pluripotent stem cell line (CSS012-A (7672)) carrying the p.G376D heterozygous mutation in the TARDBP protein

Author

Jessica Rosati, Daniela Ferrari, Angela D'Anzi, Elisa Perciballi, Mario Sabatelli, Filomena Altieri, Angelo L. Vescovi, Laura Bernardini, Barbara Torres, Serena Lattante, D'Anzi, A, Altieri, F, Perciballi, E, Ferrari, D, Torres, B, Bernardini, L, Lattante, S, Sabatelli, M, Vescovi, A, and Rosati, J

Subjects
0301 basic medicine, QH301-705.5, Cellular differentiation, Induced Pluripotent Stem Cells, TARDBP, hiPSC, familial ALS, Germ layer, Biology, medicine.disease_cause, Settore MED/03 - GENETICA MEDICA, TARDBP, Induced Pluripotent Stem Cell, hiPSC, Cell Line, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Biology (General), Induced pluripotent stem cell, Mutation, Genetic heterogeneity, Amyotrophic Lateral Sclerosis, Cell Differentiation, Cell Biology, General Medicine, Fibroblasts, Phenotype, Cell biology, 030104 developmental biology, Cell culture, Fibroblast, familial ALS, 030217 neurology & neurosurgery, Developmental Biology, Human, Amyotrophic Lateral Sclerosi
Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative condition with phenotypic and genetic heterogeneity. It is characterized by the selective vulnerability and the progressive loss of the neural population. Here, an induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of an individual carrying the p.G376D mutation in the TDP-43 protein. Fibroblasts were reprogrammed using non-integrating episomal plasmids. There were no karyotype abnormalities, and iPSCs successfully differentiated into all three germ layers. This cell line may prove useful in the study of the pathogenic mechanisms that underpin ALS syndrome.

Published
2021

83. HFE p.H63D polymorphism does not influence ALS phenotype and survival

Author

Chiò, Adriano, Mora, Gabriele, Sabatelli, Mario, Caponnetto, Claudia, Lunetta, Christian, Traynor, Bryan J., Johnson, Janel O., Nalls, Mike A., Calvo, Andrea, Moglia, Cristina, Borghero, Giuseppe, La Bella, Vincenzo, Volanti, Paolo, Simone, Isabella, Salvi, Fabrizio, Logullo, Francesco O., Nilo, Riva, Giannini, Fabio, Mandrioli, Jessica, Tanel, Raffaella, Murru, Maria Rita, Mandich, Paola, Zollino, Marcella, Conforti, Francesca L., Penco, Silvana, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Logroscino, Giancarlo, Bartolomei, Ilaria, Capasso, Margherita, Mancardi, Gianluigi, Origone, Paola, Marinou, Kalliopi, Sideri, Riccardo, Mosca, Lorena, Pinter, Giuseppe Lauria, Corbo, Massimo, Fini, Nicola, Georgoulopoulou, Eleni, Tremolizzo, Lucio, Piccirillo, Giovanni, Cristillo, Viviana, Spataro, Rossella, Colletti, Tiziana, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Santarelli, Marialuisa, Petrucci, Antonio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Ilardi, Antonio, Bertuzzo, Davide, Pisano, Fabrizio, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Ticca, Anna, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Ortu, Enzo, Cau, Tea B., Loi, Daniela, MONSURRO', Maria Rosaria, TEDESCHI, Gioacchino, TROJSI, Francesca, Chiò, Adriano, Mora, Gabriele, Sabatelli, Mario, Caponnetto, Claudia, Lunetta, Christian, Traynor, Bryan J., Johnson, Janel O., Nalls, Mike A., Calvo, Andrea, Moglia, Cristina, Borghero, Giuseppe, Monsurro', Maria Rosaria, La Bella, Vincenzo, Volanti, Paolo, Simone, Isabella, Salvi, Fabrizio, Logullo, Francesco O., Nilo, Riva, Giannini, Fabio, Mandrioli, Jessica, Tanel, Raffaella, Murru, Maria Rita, Mandich, Paola, Zollino, Marcella, Conforti, Francesca L., Penco, Silvana, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Logroscino, Giancarlo, Bartolomei, Ilaria, Capasso, Margherita, Mancardi, Gianluigi, Origone, Paola, Marinou, Kalliopi, Sideri, Riccardo, Mosca, Lorena, Pinter, Giuseppe Lauria, Corbo, Massimo, Fini, Nicola, Georgoulopoulou, Eleni, Tremolizzo, Lucio, Tedeschi, Gioacchino, Trojsi, Francesca, Piccirillo, Giovanni, Cristillo, Viviana, Spataro, Rossella, Colletti, Tiziana, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Santarelli, Marialuisa, Petrucci, Antonio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Ilardi, Antonio, Bertuzzo, Davide, Pisano, Fabrizio, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Ticca, Anna, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Ortu, Enzo, Cau, Tea B., Loi, Daniela, Chio, A, Mora, G, Sabatelli, M, Caponnetto, C, Lunetta, C, Traynor, B, Johnson, J, Nalls, M, Calvo, A, Moglia, C, Borghero, G, Monsurro, M, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F, Nilo, R, Giannini, F, Mandrioli, J, Tanel, R, Murru, M, Mandich, P, Zollino, M, Conforti, F, Penco, S, Brunetti, M, Barberis, M, Restagno, G, Logroscino, G, Bartolomei, I, Capasso, M, Mancardi, G, Origone, P, Marinou, K, Sideri, R, Mosca, L, Pinter, G, Corbo, M, Fini, N, Georgoulopoulou, E, Tremolizzo, L, Tedeschi, G, Trojsi, F, Piccirillo, G, Cristillo, V, Spataro, R, Colletti, T, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Battistini, S, Ricci, C, Benigni, M, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Bertuzzo, D, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Ticca, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Ortu, E, Cau, T, and Loi, D

Subjects
Male, Aging, Survival, Settore MED/03 - GENETICA MEDICA, Mice, Superoxide Dismutase-1, C9orf72, HFE polymorphism, Amyotrophic lateral sclerosis, HFE polymorphisms, Phenotype, SOD1, Aged, Alleles, Amyotrophic Lateral Sclerosis, Animals, Disease Progression, Female, Hemochromatosis Protein, Histocompatibility Antigens Class I, Humans, Italy, Membrane Proteins, Middle Aged, Polymorphism, Genetic, Superoxide Dismutase, Survival Rate, Genetic Association Studies, Membrane Protein, Allele, Neurology (clinical), Neuroscience (all), Developmental Biology, Geriatrics and Gerontology, General Neuroscience, phenotype, survival, Human, medicine.medical_specialty, Genetic Association Studie, Biology, TARDBP, Article, Genetic, Internal medicine, medicine, Polymorphism, Survival rate, Amyotrophic lateral sclerosi, Animal, nutritional and metabolic diseases, medicine.disease, Minor allele frequency, Endocrinology, Immunology
Abstract

It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients.

Published
2015
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84. ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry

Author

Borghero, Giuseppe, Pugliatti, Maura, Marrosu, Francesco, Marrosu, Maria Giovanna, Murru, Maria Rita, Floris, Gianluca, Cannas, Antonino, Parish, Leslie D., Cau, Tea B., Loi, Daniela, Ticca, Anna, Traccis, Sebastiano, Manera, Umberto, Canosa, Antonio, Moglia, Cristina, Calvo, Andrea, Barberis, Marco, Brunetti, Maura, Renton, Alan E., Nalls, Mike A., Traynor, Bryan J., Restagno, Gabriella, Chiò, Adriano, Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Mandich, Paola, Origone, Paola, Conforti, Francesca L., Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Lunetta, Christian, Penco, Silvana, Mosca, Lorena, Nilo, Riva, Pinter, Giuseppe Lauria, Corbo, Massimo, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Georgoulopoulou, Eleni, Tremolizzo, Lucio, Maria Rosaria Monsurrò, Null, Tedeschi, Gioacchino, Cristillo, Viviana, la Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Santarelli, Marialuisa, Petrucci, Antonio, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Ilardi, Antonio, Bertuzzo, Davide, Tanel, Raffaella, Pisano, Fabrizio, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Pirisi, Angelo, Occhineri, Patrizia, Ortu, Enzo, Borghero, G, Pugliatti, M, Marrosu, F, Marrosu, M, Murru, M, Floris, G, Cannas, A, Parish, L, Cau, T, Loi, D, Ticca, A, Traccis, S, Manera, U, Canosa, A, Moglia, C, Calvo, A, Barberis, M, Brunetti, M, Renton, A, Nalls, M, Traynor, B, Restagno, G, Chiò, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Capasso, M, Caponnetto, C, Mancardi, G, Mandich, P, Origone, P, Conforti, F, Mora, G, Marinou, K, Sideri, R, Lunetta, C, Penco, S, Mosca, L, Nilo, R, Pinter, G, Corbo, M, Volanti, P, Mandrioli, J, Fini, N, Georgoulopoulou, E, Tremolizzo, L, Monsurròad, M, Tedeschi, G, Cristillo, V, la Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Santarelli, M, Petrucci, A, Giannini, F, Battistini, S, Ricci, C, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Ilardi, A, Bertuzzo, D, Tanel, R, Pisano, F, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Pirisi, A, Occhineri, P, and Ortu, E

Subjects
Male, Aging, Amyotrophic lateral sclerosis, Ataxin 2 gene, Genetic modifier, Neurology (clinical), Neuroscience (all), Developmental Biology, Geriatrics and Gerontology, Genetic Association Studie, Biology, Settore MED/03 - GENETICA MEDICA, Article, NO, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, medicine, Humans, Risk factor, 10. No inequality, Gene, Amyotrophic Lateral Sclerosis, Ataxin-2, Female, Italy, Middle Aged, Survival Rate, Trinucleotide Repeat Expansion, Genetic Association Studies, Phenotype, Amyotrophic lateral sclerosi, 030304 developmental biology, Genetics, 0303 health sciences, Risk Factor, Medicine (all), General Neuroscience, Healthy subjects, medicine.disease, Trinucleotide repeat expansion, 030217 neurology & neurosurgery, Human
Abstract

Intermediate-length CAG expansions (encoding 27-33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that >=31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The frequency of >=31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with >=31 polyQ repeats had a spinal onset versus 73.3% of patients with =31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival.

Published
2015
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85. Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients

Author

Domenica Battaglia, Roseline Caumes, Matteo Della Monica, Giuseppe Marangi, Marni J. Falk, Manuela Priolo, Patrick Edery, Maria Chiara Stefanini, Emanuela Ponzi, Beatrice Oneda, Daniela Orteschi, Raymon Vijzelaar, Holly Dubbs, Sulagna C. Saitta, Matthew A. Deardorff, Serena Lattante, Marcella Zollino, Mattia Gentile, Francesca Scarano, Massimiliano Rossi, Maria Piccione, Omar A. Abdul-Rahman, Eugenio Mercuri, Marina Murdolo, Ilaria Contaldo, Giuseppe Zampino, Stefania Ricciardi, Anita Rauch, Elaine H. Zackai, Giovanni Corsello, Zollino, M., Marangi, G., Ponzi, E., Orteschi, D., Ricciardi, S., Lattante, S., Murdolo, M., Battaglia, D., Contaldo, I., Mercuri, E., Stefanini, M., Caumes, R., Edery, P., Rossi, M., Piccione, M., Corsello, G., Della Monica, M., Scarano, F., Priolo, M., Gentile, M., Zampino, G., Vijzelaar, R., Abdulrahman, O., Rauch, A., Oneda, B., Deardorff, M., Saitta, S., Falk, M., Dubbs, H., and Zackai, E.

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, genotype-phenotype correlations, Koolen De Vries syndrome, KANSL1 mutation, Haploinsufficiency, Biology, Settore MED/03 - GENETICA MEDICA, Severity of Illness Index, Craniofacial Abnormalities, Young Adult, Seizures, Molecular genetics, Genetics, medicine, Humans, Abnormalities, Multiple, Language Development Disorders, Child, Genetics (clinical), Genetic Association Studies, Optic nerve hypoplasia, Fetal Growth Retardation, Point mutation, Macrocephaly, Infant, Nuclear Proteins, Syndrome, clinical heterogeneity, Smith–Magenis syndrome, medicine.disease, Child, Preschool, Speech delay, Female, medicine.symptom, Chromosome Deletion, Smith-Magenis Syndrome, Chromosomes, Human, Pair 17, 17q21.31 deletion
Abstract

Background The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype–phenotype correlations and phenotypic variability have yet to be fully clarified. Methods We report genotype–phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation , 3 of whom were not previously reported. Results The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations. Conclusions In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.

Published
2015

86. ATXN2 trinucleotide repeat length correlates with risk of ALS

Author

Pietro Fratta, Aleksey Shatunov, Isabelle Le Ber, Vincenzo La Bella, Owen A. Ross, Peter M. Andersen, Tim Van Langenhove, François Salachas, Monica Forzan, John Powell, Jan H. Veldink, Andrea Malaspina, Claire Troakes, Maria del Mar Amador, Christine Van Broeckhoven, Nancy M. Bonini, Stéphanie Millecamps, Daniel Stahl, Cinzia Gellera, Aaron D. Gitler, John Hardy, Vincent Meininger, Giovanni Stevanin, Katie Sidle, Serena Lattante, Gianni Sorarù, Ben Gaastra, Leonard H. van den Berg, Christopher Shaw, Philip Van Damme, Guy A. Rouleau, Safa Al-Sarraj, Bing-Wen Soong, Richard W. Orrell, Maryam Shoai, Yi-Chung Lee, Isabella Fogh, Hussein Daoud, Rosa Rademakers, Wim Robberecht, Ashley R. Jones, Wouter van Rheenen, Ammar Al-Chalabi, Bradley N. Smith, Francesca Luisa Conforti, Edor Kabashi, William Sproviero, Sproviero, W., Shatunov, A., Stahl, D., Shoai, M., van Rheenen, W., Jones, A., Al Sarraj, S., Andersen, P., Bonini, N., Conforti, F., Van Damme, P., Daoud, H., Del Mar Amador, M., Fogh, I., Forzan, M., Gaastra, B., Gellera, C., Gitler, A., Hardy, J., Fratta, P., LA BELLA, V., Le Ber, I., Van Langenhove, T., Lattante, S., Lee, Y., Malaspina, A., Meininger, V., Millecamps, S., Orrell, R., Rademakers, R., Robberecht, W., Rouleau, G., Ross, O., Salachas, F., Sidle, K., Smith, B., Soong, B., Sorarù, G., Stevanin, G., Kabashi, E., Troakes, C., van Broeckhoven, C., Veldink, J., van den Berg, L., Shaw, C., Powell, J., and Al Chalabi, A.

Subjects
Male, Expansion, 0301 basic medicine, Aging, ATXN2 gene, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Trinucleotide Repeats, Genetic Report Abstract, Amyotrophic lateral sclerosis, Ataxin-2, Genetics, CAG, General Neuroscience, ATXN2, Triplet, 3. Good health, Female, Psychology, Neurovetenskaper, Risk, Neuroscience(all), Age of onset, Clinical Neurology, 03 medical and health sciences, SCA2, Trinucleotide repeat, Journal Article, medicine, Humans, Allele, Alleles, Genetic Association Studies, Amyotrophic lateral sclerosi, Intermediate expansion, Neuroscience (all), Neurosciences, Exponential risk, Case-control study, medicine.disease, Clinical neurology, Ageing, 030104 developmental biology, Case-Control Studies, Human medicine, Neurology (clinical), ALS, Geriatrics and Gerontology, Trinucleotide Repeat Expansion, Trinucleotide repeat expansion, Neuroscience, 030217 neurology & neurosurgery, Meta-Analysis, Developmental Biology
Abstract

We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10(-18)), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R(2) = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk. publisher: Elsevier articletitle: ATXN2 trinucleotide repeat length correlates with risk of ALS journaltitle: Neurobiology of Aging articlelink: http://dx.doi.org/10.1016/j.neurobiolaging.2016.11.010 content_type: article copyright: © 2016 The Author(s). Published by Elsevier Inc. ispartof: Neurobiology of Aging vol:51 pages:178- ispartof: location:United States status: published

Published
2017
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87. Replication of association of CHRNA4 rare variants with sporadic amyotrophic lateral sclerosis: the Italian multicentre study

Author

Ettore Capoluongo, Marcella Zollino, Christian Lunetta, Jessica Mandrioli, Paolo Zeppilli, Andrea Calvo, Massimo Corbo, Paolo Maria Rossini, Serena Lattante, Alessandra Del Grande, Mario Sabatelli, Amelia Conte, Silvana Penco, Gabriella Restagno, Adriano Chiò, Giuseppe Marangi, Alessandra Bizzarro, Fabio Giannini, Marco Luigetti, Giovanni Neri, Gabriele Mora, Stefania Battistini, Sabatelli, M, Lattante, S, Conte, A, Marangi, G, Luigetti, M, Del Grande, A, Chio, A, Corbo, M, Giannini, F, Mandrioli, J, Mora, G, Calvo, A, Restagno, G, Lunetta, C, Penco, S, Battistini, S, Zeppilli, P, Bizzarro, A, Capoluongo, E, Neri, G, Rossini, Pm, and Zollino, M

Subjects
Adult, Male, Biology, Receptors, Nicotinic, Neuroprotection, Evolution, Molecular, DNA, Genetics, Risk, Young Adult, medicine, Confidence Intervals, Odds Ratio, Animals, Humans, genetics, Genetic Predisposition to Disease, Amyotrophic lateral sclerosis, Gene, amyotrophic lateral sclerosis, Genetic Association Studies, Acetylcholine receptor, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Glutamate receptor, General Medicine, nAchR, Middle Aged, medicine.disease, Settore MED/26 - NEUROLOGIA, Nicotinic agonist, Neurology, Italy, Cohort, Mutation, Female, Neurology (clinical), ALS, α4 subunit
Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels widely expressed throughout the mammalian brain, including bulbar and spinal motor neurons. They are involved in neuroprotection and in control of release of many neurotransmitters, including glutamate. Previous data raised the hypothesis that rare variants in the region coding the intracellular loop subunits of nAChRs might represent one of several genetic risk factors for SALS. The aim of present study was to replicate the study in an independent cohort of ALS patients. We analysed 718 sporadic ALS patients from five Italian ALS centres and 1300 ethnically matched controls. We focused primarily on CHRNA4, encoding alpha 4 subunit, since most mutations were previously detected in this gene. We observed a significant association between CHRNA4 mutations and ALS (OR 2.91; 95% CI 1.4080-6.0453; p = 0.0056). Most mutations detected in patients were not present in the dbSNP134 and in 3500 ethnically matched control chromosomes and affected evolutionary conserved amino acid residues. In conclusion, the present data confirm that CHRNA4 variants are overrepresented in SALS strengthening the hypothesis can they act as predisposing genetic factors for SALS.

Published
2012

88. Intermolecular sequential energy transfer in thin films of a white emitting copolymer

Author

S. Lattante, Marco Anni, R. Cingolani, M. M. De Kok, Giuseppe Gigli, Gigli, Giuseppe, Anni, Marco, Lattante, S, DE KOK, Mm, and Cingolani, Roberto

Subjects
chemistry.chemical_classification, Resonant inductive coupling, Photoluminescence, Materials science, DEVICES, Physics and Astronomy (miscellaneous), Intermolecular force, Polymer, Photochemistry, Förster resonance energy transfer, chemistry, OXADIAZOLE, Excited state, Intramolecular force, Copolymer, ELECTROLUMINESCENCE, MOIETIES, LIGHT EMISSION, POLYMERS, DIODES
Abstract

The authors investigated the energy transfer between the chromophors of a white emitting polyspirobifluorene copolymer containing a blue emitting backbone, a green, and a red emitting dye. They demonstrate that the green dye is mainly excited by blue -> green Forster resonant energy transfer (FRET), with a Forster radius R-0bg=35 A. The red dye is instead excited by direct blue -> red FRET (R-0br=21 A) and by sequential blue -> green -> red FRET (R-0gr=31 A). Finally, the authors show that the FRET processes, fundamental to have white emission, are of intermolecular nature, while intramolecular energy migration and transfer are negligible.

Published
2006

89. Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.

Author

Sabatelli M, Cerri F, Zuccarino R, Patanella AK, Bernardo D, Bisogni G, Tanel R, Sansone V, Filosto M, Lattante S, Martello F, Doronzio PN, Stano S, Zanfini BA, Coccia M, Costantini EM, Lizio A, Lucioli G, Padovani A, Merlini GP, and Conte A

Subjects
Humans, Male, Female, Middle Aged, Aged, Neurofilament Proteins blood, Neurofilament Proteins cerebrospinal fluid, Disease Progression, Adult, Retrospective Studies, Treatment Outcome, Cohort Studies, Amyotrophic Lateral Sclerosis drug therapy, Amyotrophic Lateral Sclerosis blood, Superoxide Dismutase-1 genetics
Abstract

Background: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant., Methods: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients., Results: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy., Conclusions: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2024
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90. M 6 A reduction relieves FUS-associated ALS granules.

Author

Di Timoteo G, Giuliani A, Setti A, Biagi MC, Lisi M, Santini T, Grandioso A, Mariani D, Castagnetti F, Perego E, Zappone S, Lattante S, Sabatelli M, Rotili D, Vicidomini G, and Bozzoni I

Subjects
Humans, Cytoplasmic Granules metabolism, Fibroblasts metabolism, Adenosine metabolism, Adenosine analogs & derivatives, Methyltransferases metabolism, Methyltransferases genetics, Mutation, Inclusion Bodies metabolism, Stress Granules metabolism, Transcriptome, RNA-Binding Protein FUS metabolism, RNA-Binding Protein FUS genetics, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis pathology, Motor Neurons metabolism, Motor Neurons pathology, Induced Pluripotent Stem Cells metabolism
Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by aggregation of mutant proteins, among which the RNA binding protein FUS. Here we show that, in neuronal cells and in iPSC-derived MN expressing mutant FUS, such inclusions are significantly reduced in number and dissolve faster when the RNA m 6 A content is diminished. Interestingly, stress granules formed in ALS conditions showed a distinctive transcriptome with respect to control cells, which reverted to similar to control after m 6 A downregulation. Notably, cells expressing mutant FUS were characterized by higher m 6 A levels suggesting a possible link between m 6 A homeostasis and pathological aggregates. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, an inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS., (© 2024. The Author(s).)

Published
2024
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91. Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation.

Author

Giardina E, Mandich P, Ghidoni R, Ticozzi N, Rossi G, Fenoglio C, Tiziano FD, Esposito F, Capellari S, Nacmias B, Mineri R, Campopiano R, Di Pilla L, Sammarone F, Zampatti S, Peconi C, De Angelis F, Palmieri I, Galandra C, Nicodemo E, Origone P, Gotta F, Ponti C, Nicsanu R, Benussi L, Peverelli S, Ratti A, Ricci M, Di Fede G, Magri S, Serpente M, Lattante S, Domi T, Carrera P, Saltimbanco E, Bagnoli S, Ingannato A, Albanese A, Tagliavini F, Lodi R, Caltagirone C, Gambardella S, Valente EM, and Silani V

Abstract

Introduction: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population., Methods: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing., Results: All samples carried hexanucleotide G 4 C 2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats., Conclusion: This study describes the distribution of hexanucleotide G 4 C 2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD., Competing Interests: VS received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., Novartis Pharma AG, Zambon Biotech SA, and Asuragen. He receives or has received research supports form the Italian Ministry of Health, AriSLA, E-Rare Joint Transnational Call, and the ERN Euro-NMD. He is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology, and Exploration of Neuroprotective Therapy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Giardina, Mandich, Ghidoni, Ticozzi, Rossi, Fenoglio, Tiziano, Esposito, Capellari, Nacmias, Mineri, Campopiano, Di Pilla, Sammarone, Zampatti, Peconi, De Angelis, Palmieri, Galandra, Nicodemo, Origone, Gotta, Ponti, Nicsanu, Benussi, Peverelli, Ratti, Ricci, Di Fede, Magri, Serpente, Lattante, Domi, Carrera, Saltimbanco, Bagnoli, Ingannato, Albanese, Tagliavini, Lodi, Caltagirone, Gambardella, Valente and Silani.)

Published
2024
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92. Characterization of SOD1-DT, a Divergent Long Non-Coding RNA in the Locus of the SOD1 Human Gene.

Author

Guerra M, Meola L, Lattante S, Conte A, Sabatelli M, Sette C, and Bernardini C

Subjects
Humans, Superoxide Dismutase-1 genetics, Alleles, RNA, Long Noncoding genetics, Amyotrophic Lateral Sclerosis genetics, Neuroblastoma
Abstract

Researchers studying Amyotrophic Lateral Sclerosis (ALS) have made significant efforts to find a unique mechanism to explain the etiopathology of the different forms of the disease. However, despite several mutations associated with ALS having been discovered in recent years, the link between the mutated genes and its onset has not yet been fully elucidated. Among the genes associated with ALS, superoxide dismutase 1 (SOD1) was the first to be identified, but its role in the etiopathogenesis of the disease is still unclear. In recent years, research has been focused on the non-coding part of the genome to fully understand the mechanisms underlying gene regulation. Non-coding RNAs are conserved molecules and are not usually translated in protein. A total of 98% of the human genome is composed of non-protein coding sequences with roles in the transcriptional and post-transcriptional regulation of gene expression. In this study, we characterized a divergent nuclear lncRNA (SOD1-DT) transcribed in the antisense direction from the 5' region of the SOD1 coding gene in both the SH-SY5Y cell line and fibroblasts derived from ALS patients. Interestingly, this lncRNA seems to regulate gene expression, since its inhibition leads to the upregulation of surrounding genes including SOD1. SOD1-DT represents a very complex molecule, displaying allelic and transcriptional variability concerning transposable elements (TEs) included in its sequence, widening the scenario of gene expression regulation in ALS disease.

Published
2023
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93. Evaluating the contribution of the gene TARDBP in Italian patients with amyotrophic lateral sclerosis.

Author

Lattante S, Sabatelli M, Bisogni G, Marangi G, Doronzio PN, Martello F, Renzi AG, Del Giudice E, Leon A, Cimbolli P, Marchione D, Costantino U, Lucioli G, Bernardo D, Meleo E, Patanella AK, Romano A, Zollino M, and Conte A

Subjects
Humans, DNA-Binding Proteins genetics, Genetic Association Studies, Mutation genetics, Phenotype, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism
Abstract

Background and Objectives: Genetic variants in the gene TARDBP, encoding TDP-43 protein, are associated with amyotrophic lateral sclerosis (ALS) in familial (fALS) and sporadic (sALS) cases. Objectives of this study were to assess the contribution of TARDBP in a large cohort of Italian ALS patients, to determine the TARDBP-associated clinical features and to look for genotype-phenotype correlation and penetrance of the mutations., Methods: A total of 1992 Italian ALS patients (193 fALS and 1799 sALS) were enrolled in this study. Sanger sequencing of TARDBP gene was performed in patients and, when available, in patients' relatives., Results: In total, 13 different rare variants were identified in 43 index cases (10 fALS and 33 sALS) with a cumulative mutational frequency of 2.2% (5.2% of fALS, 1.8% of sALS). The most prevalent variant was the p.A382T followed by the p.G294V. Cognitive impairment was detected in almost 30% of patients. While some variants, including the p.G294V and the p.G376D, were associated with restricted phenotypes, the p.A382T showed a marked clinical heterogeneity regarding age of onset, survival and association with cognitive impairment. Investigations in parents, when possible, showed that the variants were inherited from healthy carriers and never occurred de novo., Conclusions: In our cohort, TARDBP variants have a relevant frequency in Italian ALS patients and they are significantly associated with cognitive impairment. Clinical presentation is heterogeneous. Consistent genotype-phenotype correlations are limited to some mutations. A marked phenotypic variability characterizes the p.A382T variant, suggesting a multifactorial/oligogenic pathogenic mechanism., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Published
2023
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94. Analysis of STMN2 CA repeats in italian ALS patients shows no association.

Author

Doronzio PN, Lattante S, Marangi G, Martello F, Conte A, Bisogni G, Bernardo D, Patanella AK, Meleo E, Zollino M, and Sabatelli M

Subjects
Humans, Risk Factors, Genotype, Italy, Stathmin genetics, Amyotrophic Lateral Sclerosis genetics, Neurodegenerative Diseases
Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by a complex interaction of genetic and environmental factors. Recently, a polymorphic intronic CA repeat in STMN2 gene has been proposed as risk factor for ALS. The presence of long/long CA genotype, especially if one allele had 24 CA, was reported to be significantly associated with the disease in a cohort of sporadic ALS patients. We tested an Italian cohort of 366 ALS patients and 353 healthy controls and we found no association between CA length and ALS risk.

Published
2023
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95. Allele-specific silencing as therapy for familial amyotrophic lateral sclerosis caused by the p.G376D TARDBP mutation.

Author

Romano R, De Luca M, Del Fiore VS, Pecoraro M, Lattante S, Sabatelli M, La Bella V, and Bucci C

Abstract

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons. There is no treatment for this disease that affects the ability to move, eat, speak and finally breathe, causing death. In an Italian family, a heterozygous pathogenic missense variant has been previously discovered in Exon 6 of the gene TARDBP encoding the TAR DNA-binding protein 43 protein. Here, we developed a potential therapeutic tool based on allele-specific small interfering RNAs for familial amyotrophic lateral sclerosis with the heterozygous missense mutation c.1127G>A. We designed a small interfering RNA that was able to diminish specifically the expression of the exogenous Green Fluorescent Protein (TAR DNA-binding protein 43 G376D mutant protein) in HEK-293T cells but not that of the Green Fluorescent Protein (TAR DNA-binding protein 43 wild-type). Similarly, this small interfering RNA silenced the mutated allele in fibroblasts derived from patients with amyotrophic lateral sclerosis but did not silence the wild-type gene in control fibroblasts. In addition, we established that silencing the mutated allele was able to strongly reduce the pathological cellular phenotypes induced by TAR DNA-binding protein 43 G376D expression, such as the presence of cytoplasmic aggregates. Thus, we have identified a small interfering RNA that could be used to silence specifically the mutated allele to try a targeted therapy for patients carrying the p.G376D TAR DNA-binding protein 43 mutation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Published
2022
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96. Generation of an induced pluripotent stem cell line (UCSCi002-A) from a patient with a variant in TARDBP gene associated with familial amyotrophic lateral sclerosis and frontotemporal dementia.

Author

Martello F, Lattante S, Doronzio PN, Conte A, Bisogni G, Orteschi D, Luigetti M, Marrucci MA, Zollino M, Sabatelli M, and Marangi G

Subjects
Humans, Mutation genetics, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Frontotemporal Dementia genetics, Induced Pluripotent Stem Cells metabolism, Neurodegenerative Diseases metabolism
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively affects motor neurons. In 20% of cases, ALS appears in comorbidity with frontotemporal dementia (FTD). We generated patient-derived-induced Pluripotent Stem Cells (iPSCs), from an ALS/FTD patient. The patient had a familial form of the disease and a missense variant in TARDBP gene. We used an established protocol based on Sendai virus to reprogram fibroblasts. We confirmed the stemness and the pluripotency of the iPSC clones, thus generating embryoid bodies. We believe that the iPSC line carrying a TARDBP mutation could be a valuable tool to investigate TDP-43 proteinopathy linked to ALS., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2022
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97. Characterization of the p.L145F and p.S135N Mutations in SOD1: Impact on the Metabolism of Fibroblasts Derived from Amyotrophic Lateral Sclerosis Patients.

Author

Perciballi E, Bovio F, Rosati J, Arrigoni F, D'Anzi A, Lattante S, Gelati M, De Marchi F, Lombardi I, Ruotolo G, Forcella M, Mazzini L, D'Alfonso S, Corrado L, Sabatelli M, Conte A, De Gioia L, Martino S, Vescovi AL, Fusi P, and Ferrari D

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of the upper and lower motor neurons (MNs). About 10% of patients have a family history (familial, fALS); however, most patients seem to develop the sporadic form of the disease (sALS). SOD1 (Cu/Zn superoxide dismutase-1) is the first studied gene among the ones related to ALS. Mutant SOD1 can adopt multiple misfolded conformation, lose the correct coordination of metal binding, decrease structural stability, and form aggregates. For all these reasons, it is complicated to characterize the conformational alterations of the ALS-associated mutant SOD1, and how they relate to toxicity. In this work, we performed a multilayered study on fibroblasts derived from two ALS patients, namely SOD1 L145F and SOD1 S135N , carrying the p.L145F and the p.S135N missense variants, respectively. The patients showed diverse symptoms and disease progression in accordance with our bioinformatic analysis, which predicted the different effects of the two mutations in terms of protein structure. Interestingly, both mutations had an effect on the fibroblast energy metabolisms. However, while the SOD1 L145F fibroblasts still relied more on oxidative phosphorylation, the SOD1 S135N fibroblasts showed a metabolic shift toward glycolysis. Our study suggests that SOD1 mutations might lead to alterations in the energy metabolism.

Published
2022
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98. Adult phenotype in Koolen-de Vries/ KANSL1 haploinsufficiency syndrome.

Author

Amenta S, Frangella S, Marangi G, Lattante S, Ricciardi S, Doronzio PN, Orteschi D, Veredice C, Contaldo I, Zampino G, Gentile M, Scarano E, Graziano C, and Zollino M

Subjects
Abnormalities, Multiple genetics, Adult, Chromosome Deletion, Chromosomes, Human, Pair 17 genetics, Female, Humans, Intellectual Disability genetics, Male, Middle Aged, Phenotype, Prognosis, Retrospective Studies, Young Adult, Abnormalities, Multiple pathology, Intellectual Disability pathology, Nuclear Proteins genetics
Abstract

Background: Koolen-de Vries syndrome (KdVS) is a multisystem neurodevelopmental disorder caused by 17q21.31 deletions or mutations in KANSL1 . It was mainly described in children., Methods: A retrospective study on 9 subjects aged 19-45 years and revision of 18 literature patients, with the purpose to get insights into the phenotypic evolution with time, and into the clinical manifestations in adulthood., Results: Seven patients had a 17q21.31 deletion and two a point mutation in KANSL1 . All had intellectual disability, which was mild in five (56%) and moderate in four (44%). Epilepsy was diagnosed in four subjects (44%), with onset from 1 to 7 years and full remission before 9 years in 3/4 patients. Scoliosis affected seven individuals (77.7%) and it was substantially stable with age in 5/7 patients, allowing for simple daily activities. Two subjects had severely progressive scoliosis, which was surgically corrected. Overweight or true obesity did occur after puberty in six patients (67%). Behaviour abnormalities were recorded in six patients (67%). The facial phenotype slightly evolved with time to include thick eyebrows, elongated nose and pronounced pointed chin. Despite behaviour abnormalities, happy disposition and sociable attitudes were common. Half of patients had fluent language and were good at writing and reading. Rich language, although limited to single words or short sentences, and very limited or absent skills in writing and reading were observed in the remaining patients. Autonomy in daily activities and personal care was usually limited., Conclusions: Distinctive features in adult KdVS subjects include intellectual disability, overweight/obesity, behaviour abnormalities with preserved social interest, ability in language, slight worsening of the facial phenotype and no seizures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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99. FUS mutations dominate TBK1 mutations in FUS/TBK1 double-mutant ALS/FTD pedigrees.

Author

Brenner D, Müller K, Lattante S, Yilmaz R, Knehr A, Freischmidt A, Ludolph AC, Andersen PM, and Weishaupt JH

Subjects
Humans, Mutation, Pedigree, Protein Serine-Threonine Kinases genetics, RNA-Binding Protein FUS genetics, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics
Abstract

Mutations in FUS and TBK1 often cause aggressive early-onset amyotrophic lateral sclerosis (ALS) or a late-onset ALS and/or frontotemporal dementia (FTD) phenotype, respectively. Co-occurrence of mutations in two or more Mendelian ALS/FTD genes has been repeatedly reported. However, little is known how two pathogenic ALS/FTD mutations in the same patient interact to shape the final phenotype. We screened 28 ALS patients with a known FUS mutation by whole-exome sequencing and targeted evaluation for mutations in other known ALS genes followed by genotype-phenotype correlation analysis of FUS/TBK1 double-mutant patients. We report on new and summarize previously published FUS and TBK1 double-mutant ALS/FTD patients and their families. We found that, within a family, mutations in FUS cause ALS while TBK1 single mutations are observed in FTD patients. FUS/TBK1 double mutations manifested as ALS and without a manifest difference regarding age at onset and disease duration when compared to FUS single-mutant individuals. In conclusion, TBK1 and FUS variants do not seem to interact in a simple additive way. Rather, the phenotype of FUS/TBK1 double-mutant patients appears to be dominated by the FUS mutation., (© 2021. The Author(s).)

Published
2022
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100. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration.

Author

Barbier M, Camuzat A, Hachimi KE, Guegan J, Rinaldi D, Lattante S, Houot M, Sánchez-Valle R, Sabatelli M, Antonell A, Molina-Porcel L, Clot F, Couratier P, van der Ende E, van der Zee J, Manzoni C, Camu W, Cazeneuve C, Sellal F, Didic M, Golfier V, Pasquier F, Duyckaerts C, Rossi G, Bruni AC, Alvarez V, Gómez-Tortosa E, de Mendonça A, Graff C, Masellis M, Nacmias B, Oumoussa BM, Jornea L, Forlani S, Van Deerlin V, Rohrer JD, Gelpi E, Rademakers R, Van Swieten J, Le Guern E, Van Broeckhoven C, Ferrari R, Génin E, Brice A, and Le Ber I

Subjects
Adult, Age of Onset, Aged, Aged, 80 and over, Cohort Studies, Female, Frontotemporal Lobar Degeneration epidemiology, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, C9orf72 Protein genetics, Frontotemporal Lobar Degeneration diagnosis, Frontotemporal Lobar Degeneration genetics, Genes, X-Linked genetics, Genome-Wide Association Study methods, Membrane Proteins genetics, Nerve Tissue Proteins genetics
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2021
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