Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients Mario Sabatelli, Federica Cerri, Riccardo Zuccarino, Agata Katia Patanella, Daniela Bernardo, Giulia Bisogni, Raffaella Tanel, Valeria Sansone, Massimiliano Filosto, Serena Lattante, Francesco Martello, Paolo Niccolò Doronzio, Salvatore Stano, Bruno Antonio Zanfini, Michela Coccia, Emanuele Maria Costantini, Andrea Lizio, Gabriele Lucioli, Alessandro Padovani, Gian Paolo Merlini, Amelia Conte Journal of Neurology, 2024
Evaluating the contribution of the gene TARDBP in Italian patients with amyotrophic lateral sclerosis Serena Lattante, Mario Sabatelli, Giulia Bisogni, Giuseppe Marangi, Paolo Niccolò Doronzio, Francesco Martello, Anna Gloria Renzi, Elda Del Giudice, Alberta Leon, Paola Cimbolli, Daniela Marchione, Umberto Costantino, Gabriele Lucioli, Daniela Bernardo, Emiliana Meleo, Agata Katia Patanella, Angela Romano, Marcella Zollino, Amelia Conte European Journal of Neurology, 2023 BACKGROUND AND OBJECTIVES Genetic variants in the gene TARDBP, encoding TDP-43 protein, are associated to 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 to 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. DISCUSSION In our cohort, TARDBP variants have a relevant frequency in Italian ALS patients and they are significantly associated to 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.
Analysis of STMN2 CA repeats in italian ALS patients shows no association Paolo Niccolò Doronzio, Serena Lattante, Giuseppe Marangi, Francesco Martello, Amelia Conte, Giulia Bisogni, Daniela Bernardo, Agata Katia Patanella, Emiliana Meleo, Marcella Zollino, Mario Sabatelli Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2023 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.
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 Francesco Martello, Serena Lattante, Paolo Niccolò Doronzio, Amelia Conte, Giulia Bisogni, Daniela Orteschi, Marco Luigetti, Maria Alessandra Marrucci, Marcella Zollino, Mario Sabatelli, Giuseppe Marangi Stem Cell Research, 2022 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.
Generation of an induced pluripotent stem cell line (UCSCi001-A) from a patient with early-onset amyotrophic lateral sclerosis carrying a FUS variant Francesco Martello, Serena Lattante, Paolo Niccolò Doronzio, Amelia Conte, Giulia Bisogni, Daniela Orteschi, Filomena Pirozzi, Mario Sabatelli, Marcella Zollino, Giuseppe Marangi Stem Cell Research, 2021 Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons. We generated patient-derived-induced Pluripotent Stem Cells (iPSCs), from an ALS patient affected by an early-onset and aggressive form of the disease, carrying a missense pathogenic variant in FUS gene. We reprogrammed somatic cells using an established Sendai virus protocol and we obtained clones of iPSC. We confirmed their stemness and further generated embryoid bodies, showing their potential of differentiating in all three germ layers. This iPSC line, carrying a pathogenic FUS variant, is a valuable tool to deeply investigate pathogenic mechanisms leading to ALS.
Novel variants and cellular studies on patients' primary fibroblasts support a role for NEK1 missense variants in ALS pathogenesis Serena Lattante, Paolo Niccolò Doronzio, Amelia Conte, Giuseppe Marangi, Francesco Martello, Giulia Bisogni, Emiliana Meleo, Davide Colavito, Elda Del Giudice, Agata Katia Patanella, Daniela Bernardo, Angela Romano, Marcella Zollino, Mario Sabatelli Human Molecular Genetics, 2021 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.
Production and characterization of human induced pluripotent stem cells (iPSC) CSSi007-A (4383) from Joubert Syndrome Filomena Altieri, Angela D'Anzi, Francesco Martello, Silvia Tardivo, Iolanda Spasari, Daniela Ferrari, Laura Bernardini, Giuseppe Lamorte, Gianluigi Mazzoccoli, Enza Maria Valente, Angelo Luigi Vescovi, Jessica Rosati Stem Cell Research, 2019 Joubert syndrome (JS) is an autosomal recessive neurodevelopmental disorder, characterized by congenital cerebellar and brainstem defects, belonging to the group of disorders known as ciliopathies, which are caused by mutations in genes encoding proteins of the primary cilium and basal body. Human induced pluripotent stem cells (hiPSCs) from a patient carrying a homozygous missense mutation (c.2168G > A) in AHI1, the first gene to be associated with JS, were produced using a virus-free protocol.
