Andrea Ghezzi1, Ilaria Martinelli2,3, Serena Carra1, Laura Mediani1, Elisabetta Zucchi1,4, Cecilia Simonini4, Giulia Gianferrari1, Nicola Fini4, Cristina Cereda5, Cinzia Gellera6, Viviana Pensato6, Jessica Mandrioli1,4. 1. Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. 2. Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy. martinelli.ilaria88@gmail.com. 3. Department of Neurosciences, Azienda Ospedaliero-Universitaria Di Modena, Modena, Italy. martinelli.ilaria88@gmail.com. 4. Department of Neurosciences, Azienda Ospedaliero-Universitaria Di Modena, Modena, Italy. 5. Genomic and Post-Genomic Unit IRCCS - Mondino Foundation, Pavia, Italy. 6. Unit of Medical Genetics and Neurogenetics - Fondazione, IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
Abstract
BACKGROUND: ALS symptoms have been previously described only in the context of ATXN2 CAG expansions, whereas missense mutations of the gene have never been described in ALS patients. CASE PRESENTATION: We identified a novel missense mutation (c.2860C > T) of ATXN2, for which in silico analysis showed a possible pathogenic effect on protein expression, in a patient presenting an aggressive disease phenotype. DISCUSSION: Our findings raise the possibility for unknown genetic factors interacting with ATXN2 mutations, or for an autonomous pathogenic role for this specific point mutation in ATXN2 gene in driving the clinical phenotype toward ALS. We also found that stress granules in the fibroblasts from the patient entrapped higher amounts of defective ribosomal products compared to fibroblasts from three healthy subjects, suggesting that ATXN2 mutation-related toxicity may have implication in protein quality control.
BACKGROUND: ALS symptoms have been previously described only in the context of ATXN2 CAG expansions, whereas missense mutations of the gene have never been described in ALS patients. CASE PRESENTATION: We identified a novel missense mutation (c.2860C > T) of ATXN2, for which in silico analysis showed a possible pathogenic effect on protein expression, in a patient presenting an aggressive disease phenotype. DISCUSSION: Our findings raise the possibility for unknown genetic factors interacting with ATXN2 mutations, or for an autonomous pathogenic role for this specific point mutation in ATXN2 gene in driving the clinical phenotype toward ALS. We also found that stress granules in the fibroblasts from the patient entrapped higher amounts of defective ribosomal products compared to fibroblasts from three healthy subjects, suggesting that ATXN2 mutation-related toxicity may have implication in protein quality control.
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