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14 results on '"Lattante S"'

1. Novel variants and cellular studies on patients' primary fibroblasts support a role for NEK1 missense variants in ALS pathogenesis.

Author

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

Subjects
Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis physiopathology, Cohort Studies, Female, Fibroblasts, Humans, Loss of Function Mutation genetics, Male, Middle Aged, Mutation, Missense genetics, Primary Cell Culture, Amyotrophic Lateral Sclerosis genetics, Genetic Association Studies, Genetic Predisposition to Disease, NIMA-Related Kinase 1 genetics
Abstract

In the last few years, NEK1 has been identified as a new gene related to amyotrophic lateral sclerosis (ALS). Loss-of-function variants have been mostly described, although several missense variants exist, which pathogenic relevance remains to be established. We attempted to determine the contribution of NEK1 gene in an Italian cohort of 531 sporadic and familial amyotrophic lateral sclerosis (ALS) patients applying massive parallel sequencing technologies. We filtered results of NEK1 gene and identified 20 NEK1 rare variants (MAF < 0.01) in 22 patients. In particular, we found two novel frameshift variants (p.Glu929Asnfs*12 and p.Val1030Ilefs*23), 18 missense variants, including the p.Arg261His in three patients, and a novel variant in the start codon, the p.Met1?, which most likely impairs translation initiation. To clarify the role of NEK1 missense variants we investigated NEK1 expression in primary fibroblast cultures. We obtained skin biopsies from four patients with NEK1 variants and we assessed NEK1 expression by western blot and immunofluorescence. We detected a decrease in NEK1 expression in fibroblasts from patients with NEK1 variants, suggesting that missense variants in NEK1 gene may have a pathogenic role. Moreover, we observed additional variants in ALS related genes in seven patients with NEK1 variants (32%), further supporting an oligogenic ALS model., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2021
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2. ATXN1 intermediate-length polyglutamine expansions are associated with amyotrophic lateral sclerosis.

Author

Lattante S, Pomponi MG, Conte A, Marangi G, Bisogni G, Patanella AK, Meleo E, Lunetta C, Riva N, Mosca L, Carrera P, Bee M, Zollino M, and Sabatelli M

Subjects
Alleles, Amyotrophic Lateral Sclerosis pathology, C9orf72 Protein genetics, Cohort Studies, Female, Heterozygote, Humans, Italy, Male, Middle Aged, Nerve Degeneration genetics, Risk Factors, Amyotrophic Lateral Sclerosis etiology, Amyotrophic Lateral Sclerosis genetics, Ataxin-1 genetics, DNA Repeat Expansion genetics, Genetic Association Studies, Peptides genetics
Abstract

To clarify the possible involvement of intermediate ATXN1 alleles as risk factors for amyotrophic lateral sclerosis (ALS), we tested ATXN1 in a cohort of 1146 Italian ALS patients, previously screened for variants in other ALS genes, and in 529 controls. We detected ATXN1 alleles with ≥33 polyglutamine repeats in 105 of 1146 patients (9.16%) and 29 of 529 controls (5.48%) (p = 0.003). The frequency of ATXN1 alleles with ≥33 polyglutamine repeats was particularly high in the group of ALS patients carrying the C9orf72 expansion (12/59, 20.3%). We confirmed this result in an independent cohort of C9orf72 Italian patients (10/80 cases, 12.5%), thus finding a cumulative frequency of ATXN1 expansion of 15.82% in C9orf72 carriers (p = 2.40E-05). Our results strongly support the hypothesis that ATXN1 could act as a disease risk gene in ALS, mostly in C9orf72 expansion carriers. Further studies are needed to confirm our results and to define the mechanism by which ATXN1 might contribute to neuronal degeneration leading to ALS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2018
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3. ATXN2 trinucleotide repeat length correlates with risk of ALS.

Author

Sproviero W, Shatunov A, Stahl D, Shoai M, van Rheenen W, Jones AR, Al-Sarraj S, Andersen PM, Bonini NM, Conforti FL, Van Damme P, Daoud H, Del Mar Amador M, Fogh I, Forzan M, Gaastra B, Gellera C, Gitler AD, Hardy J, Fratta P, La Bella V, Le Ber I, Van Langenhove T, Lattante S, Lee YC, Malaspina A, Meininger V, Millecamps S, Orrell R, Rademakers R, Robberecht W, Rouleau G, Ross OA, Salachas F, Sidle K, Smith BN, Soong BW, Sorarù G, Stevanin G, Kabashi E, Troakes C, van Broeckhoven C, Veldink JH, van den Berg LH, Shaw CE, Powell JF, and Al-Chalabi A

Subjects
Age of Onset, Alleles, Case-Control Studies, Female, Humans, Male, Risk, Amyotrophic Lateral Sclerosis genetics, Ataxin-2 genetics, Genetic Association Studies, Trinucleotide Repeat Expansion genetics, Trinucleotide Repeats genetics
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., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2017
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4. Matrin 3 variants are frequent in Italian ALS patients.

Author

Marangi G, Lattante S, Doronzio PN, Conte A, Tasca G, Monforte M, Patanella AK, Bisogni G, Meleo E, La Spada S, Zollino M, and Sabatelli M

Subjects
Aged, Cohort Studies, Female, Humans, Italy, Male, Middle Aged, Amyotrophic Lateral Sclerosis genetics, Genetic Association Studies, Genetic Variation genetics, Nuclear Matrix-Associated Proteins genetics, RNA-Binding Proteins genetics
Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons in the primary motor cortex, brainstem, and spinal cord. Recently, missense variants in MATR3 were identified in familial and sporadic ALS patients, but very few additional ALS patients have been reported so far. The p.S85C MATR3 variant was previously associated to a different phenotype, namely a distal myopathy associated with dysphagia and dysphonia. Here, we assessed the contribution of MATR3 variants in a cohort of 322 Italian ALS patients. We identified 5 different missense MATR3 variants (p.Q66K, p.G153C, p.E664A, p.S707L, and p.N787S) in 6 patients (1.9%). None of our patients showed signs of myopathy at electrophysiological examination. Muscle biopsy, performed in 2 patients, showed neurogenic changes and normal nuclear staining with anti-matrin 3 antibody. Our results confirm that MATR3 variants are associated with ALS and suggest that they are more frequent in Italian ALS patients. Further studies are needed to elucidate the pathogenic significance of identified variants in sporadic and familial ALS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2017
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5. Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD).

Author

Lattante S, Ciura S, Rouleau GA, and Kabashi E

Subjects
Animals, Disease Models, Animal, Genetic Variation, Humans, Inheritance Patterns, Risk Factors, Translational Research, Biomedical, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Genetic Association Studies, Genetic Predisposition to Disease
Abstract

Several genetic causes have been recently described for neurological diseases, increasing our knowledge of the common pathological mechanisms involved in these disorders. Mutation analysis has shown common causative factors for two major neurodegenerative disorders, ALS and FTD. Shared pathological and genetic markers as well as common neurological signs between these diseases have given rise to the notion of an ALS/FTD spectrum. This overlap among genetic factors causing ALS/FTD and the coincidence of mutated alleles (including causative, risk and modifier variants) have given rise to the notion of an oligogenic model of disease. In this review we summarize major advances in the elucidation of novel genetic factors in these diseases which have led to a better understanding of the common pathogenic factors leading to neurodegeneration., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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6. Homozygous TREM2 mutation in a family with atypical frontotemporal dementia.

Author

Le Ber I, De Septenville A, Guerreiro R, Bras J, Camuzat A, Caroppo P, Lattante S, Couarch P, Kabashi E, Bouya-Ahmed K, Dubois B, and Brice A

Subjects
Adult, Brain pathology, Female, Frontotemporal Dementia pathology, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Phenotype, Frontotemporal Dementia genetics, Genetic Association Studies, Homozygote, Membrane Glycoproteins genetics, Mutation genetics, Receptors, Immunologic genetics
Abstract

TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p.Thr66Met heterozygous mutation in a new consanguineous Italian family. Two sibs had early onset autosomal recessive FTLD without severe bone disorders. Atypical signs were present in this family: early parietal and hippocampus involvement, parkinsonism, epilepsy, and corpus callosum thickness on brain magnetic resonance imaging. This study further demonstrates the implication of TREM2 mutations in FTLD phenotypes. It illustrates the variability of bone phenotype and underlines the frequency of atypical signs in TREM2 carriers. This and previous studies evidence that TREM2 mutation screening should be limited to autosomal recessive FTLD with atypical phenotypes characterized by: (1) a very young age at onset (20-50 years); (2) early parietal and hippocampal deficits; (3) the presence of seizures and parkinsonism; (4) suggestive extensive white matter lesions and corpus callosum thickness on brain magnetic resonance imaging., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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7. 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 PM, and Sabatelli M

Subjects
Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis diagnosis, Cohort Studies, DNA-Binding Proteins genetics, Female, Humans, Male, Middle Aged, Mutation genetics, Pedigree, Superoxide Dismutase genetics, Superoxide Dismutase-1, Young Adult, Amyotrophic Lateral Sclerosis etiology, Amyotrophic Lateral Sclerosis genetics, Genetic Association Studies methods
Abstract

Objectives: 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., Methods: Screening for SOD1, TARDBP, FUS, ANG, ATXN2, OPTN, and C9ORF72 was carried out in 480 consecutive patients with sporadic ALS (SALS) and in 48 familial ALS (FALS) index patients admitted to a single Italian referral center., Results: Mutations were detected in 53 patients, with a cumulative frequency of 11. Seven of them were novel. The highest frequencies of positive cases were obtained in TARDBP (2.7%), C9ORF72 (2.5%), and SOD1 (2.1%). The overall group of mutated patients was indistinguishable from that without mutations as no significant differences were observed with regard to age and site of onset, frequency of clinical phenotypes, and survival. However, by separately evaluating genotype-phenotype correlation in single genes, clinical differences were observed among different genes. Duration of disease was significantly shorter in patients harboring the C9ORF72 expansion and longer in the SOD1 group. A high frequency of predominant upper motor neuron phenotype was observed among patients with TARDBP mutations. Two patients, 1 with C9ORF72 and 1 with SOD1 mutation, had concurrent ANG mutations. Mutations were detected in 43.7% of patients with FALS., Conclusions: A considerable proportion of patients with SALS harbored mutations in major ALS genes. This result has relevant implications in clinical practice, namely in genetic counseling. The detection of double mutations in 2 patients raises the hypothesis that multiple mutations model may explain genetic architecture of SALS.

Published
2012
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8. D11Y SOD1 mutation and benign ALS: a consistent genotype-phenotype correlation.

Author

Del Grande A, Conte A, Lattante S, Luigetti M, Marangi G, Zollino M, Madia F, Bisogni G, and Sabatelli M

Subjects
Aged, Amino Acid Substitution genetics, Aspartic Acid genetics, Female, Humans, Middle Aged, Superoxide Dismutase-1, Tyrosine genetics, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis genetics, Genetic Association Studies methods, Mutation genetics, Superoxide Dismutase genetics
Abstract

We describe three sporadic ALS patients in which a D11Y SOD1 mutation was detected. All three patients disclosed a prolonged survival and a stereotypical distal limbs involvement in the initial stages of the disease. By this report we demonstrate that D11Y SOD1 mutation is associated with a peculiar phenotype and we confirm its probable pathogenetic role., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Published
2011
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9. CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients

Author

Chiò, A, Mora, G, Sabatelli, M, Caponnetto, C, Traynor, B. J, Johnson, J. O, Nalls, M. A, Calvo, A, Moglia, C, Borghero, G, Monsurrò, M. R, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F. O, Nilo, R, Battistini, S, Mandrioli, J, Tanel, R, Murru, M. R, Mandich, P, Zollino, M, Conforti, F. L, Brunetti, M, Barberis, M, Restagno, G, Penco, S, Lunetta, C, Giannini, F, Ricci, C, Mancardi, G, Bartolomei, I, Corbo, M, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Ossola, I, Logroscino, G, Tedeschi, G, Pugliatti, M, Pinter, G. L, Glynn, S, Gibbs, J. R, Cammarosano, S, Canosa, A, Manera, U, Bertuzzo, D, Ilardi, A, Marinou, K, Sideri, R, Pisano, F, Spataro, R, Colletti, T, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, M. G, Parish, L. D, Ticca, A, Pirisi, A, Ortu, E, Cau, T. B, Loi, D, Traccis, S, Fini, N, Georgoulopoulou, E, Casale, F, Marrali, G, Fuda, G, Solamone, P, Maestri, E, Mazzei, R, Cristillo, V, Puddu, R, Costantino, E, Pani, C, Caredda, C, Origone, P, Mosca, L, Capasso, M, Turri, M, Petrucci, A, Tremolizzo, L, Santarelli, M., Chiò, A, Mora, G, Sabatelli, M, Caponnetto, C, Traynor, B, Johnson, J, Nalls, M, Calvo, A, Moglia, C, Borghero, G, Monsurrò, M, La Bella, V, Volanti, P, Simone, I, Salvi, F, Logullo, F, Nilo, R, Battistini, S, Mandrioli, J, Tanel, R, Murru, M, Mandich, P, Zollino, M, Conforti, F, Brunetti, M, Barberis, M, Restagno, G, Penco, S, Lunetta, C, Giannini, F, Ricci, C, Mancardi, G, Bartolomei, I, Corbo, M, Conte, A, Luigetti, M, Lattante, S, Marangi, G, Ossola, I, Logroscino, G, Tedeschi, G, Pugliatti, M, Pinter, G, Glynn, S, Gibbs, J, Cammarosano, S, Canosa, A, Manera, U, Bertuzzo, D, Ilardi, A, Marinou, K, Sideri, R, Pisano, F, Spataro, R, Colletti, T, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, M, Parish, L, Ticca, A, Pirisi, A, Ortu, E, Cau, T, Loi, D, Traccis, S, Fini, N, Georgoulopoulou, E, Casale, F, Marrali, G, Fuda, G, Solamone, P, Maestri, E, Mazzei, R, Cristillo, V, Puddu, R, Costantino, E, Pani, C, Caredda, C, Origone, P, Mosca, L, Capasso, M, Turri, M, Petrucci, A, Tremolizzo, L, Santarelli, M, Chiò, Adriano, Mora, Gabriele, Sabatelli, Mario, Caponnetto, Claudia, 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, Battistini, Stefania, Mandrioli, Jessica, Tanel, Raffaella, Murru, Maria Rita, Mandich, Paola, Zollino, Marcella, Conforti, Francesca L., Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Penco, Silvana, Lunetta, Christian, Giannini, Fabio, Ricci, Claudia, Mancardi, Gianluigi, Bartolomei, Ilaria, Corbo, Massimo, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Ossola, Irene, Logroscino, Giancarlo, Tedeschi, Gioacchino, Pugliatti, Maura, Pinter, Giuseppe Lauria, Glynn, Shannon, Gibbs, J. Raphael, Cammarosano, Stefania, Canosa, Antonio, Manera, Umberto, Bertuzzo, Davide, Ilardi, Altonio, Marinou, Kalliopi, Sideri, Riccardo, Pisano, Fabrizio, Spataro, Rossella, Colletti, Tiziana, Floris, Gianluca, Cannas, Antonino, Piras, Valeria, Marrosu, Francesco, Marrosu, Maria Giovanna, Parish, Leslie D., Ticca, Anna, Pirisi, Angelo, Ortu, Enzo, Cau, Tea B., Loi, Daniela, Traccis, Sebastiano, Fini, Nicola, Georgoulopoulou, Eleni, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Solamone, Paolina, Maestri, Eleonora, Mazzei, Rosalucia, Cristillo, Viviana, Puddu, Roberta, Costantino, Emanuela, Pani, Carla, Caredda, Carla, Origone, Paola, Mosca, Lorena, Capasso, Margherita, Turri, Mara, Petrucci, Antonio, Tremolizzo, Luico, Santarelli, Marialaura, Chiò, A., Mora, G., Sabatelli, M., Caponnetto, C., Traynor, B., Johnson, J., Nalls, M., Calvo, A., Moglia, C., Borghero, G., Monsurrò, M., LA BELLA, V., Volanti, P., Simone, I., Salvi, F., Logullo, F., Nilo, R., Battistini, S., Mandrioli, J., Tanel, R., Murru, M., Mandich, P., Zollino, M., Conforti, F., Brunetti, M., Barberis, M., Restagno, G., Penco, S., Lunetta, C., Giannini, F., Ricci, C., Mancardi, G., Bartolomei, I., Corbo, M., Conte, A., Luigetti, M., Lattante, S., Marangi, G., Ossola, I., Logroscino, G., Tedeschi, G., Pugliatti, M., Pinter, G., Glynn, S., Gibbs, J., Cammarosano, S., Canosa, A., Manera, U., Bertuzzo, D., Ilardi, A., Marinou, K., Sideri, R., Pisano, F., Spataro, R., Colletti, T., Floris, G., Cannas, A., Piras, V., Marrosu, F., Marrosu, M., Parish, L., Ticca, A., Pirisi, A., Ortu, E., Cau, T., Loi, D., Traccis, S., Fini, N., Georgoulopoulou, E., Casale, F., Marrali, G., Fuda, G., Solamone, P., Maestri, E., Mazzei, R., Cristillo, V., Puddu, R., Costantino, E., Pani, C., Caredda, C., Origone, P., Mosca, L., Capasso, M., Turri, M., Petrucci, A., Tremolizzo, L., and Santarelli, M.

Subjects
Male, Aging, Pediatrics, medicine.medical_specialty, Pathology, Amyotrophic lateral sclerosis, CHCHD10, Familial, Sporadic, Aged, Amyotrophic Lateral Sclerosis, Cohort Studies, Female, Frontotemporal Dementia, Genetic Predisposition to Disease, Humans, Italy, Middle Aged, Mitochondrial Proteins, Genetic Association Studies, Mutation, Genetic Association Studie, Disease, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, Exon, mental disorders, medicine, Mitochondrial Protein, Dementia, Neurology (clinical), Neuroscience (all), Developmental Biology, Geriatrics and Gerontology, Amyotrophic lateral sclerosi, business.industry, General Neuroscience, medicine.disease, 3. Good health, Cohort, Cohort Studie, business, Human, Frontotemporal dementia, Cohort study
Abstract

Mutations in CHCHD10 have recently been described as a cause of frontotemporal dementia (FTD) comorbid with amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the frequency and clinical characteristics of CHCHD10 mutations in Italian patients diagnosed with familial (n= 64) and apparently sporadic ALS (n= 224). Three apparently sporadic patients were found to carry c.100C>T (p.Pro34Ser) heterozygous variant in the exon 2 of CHCHD10. This mutation had been previously described in 2 unrelated French patients with FTD-ALS. However, our patients had a typical ALS, without evidence of FTD, cerebellar or extrapyramidal signs, or sensorineural deficits. We confirm that CHCHD10 mutations account for ~1% of Italian ALS patients and are a cause of disease in subjects without dementia or other atypical clinical signs.

Published
2015
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10. 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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11. 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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12. 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

13. 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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14. 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

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