A novel mutation in the RRM2 domain of TDP-43 in a Brazilian sporadic ALS patient.

Abstract

Introduction: Amyotrophic Lateral Sclerosis (ALS) is an adult-onset progressive and fatal neurodegenerative disease that selectively affects upper and lower motor neurons. Death occurs within 3 to 5 years of onset, usually from respiratory complications. Most cases of ALS are sporadic (SALS), but familial forms of the disease (FALS) represent approximately 10% of the cases. More than 30 genes have been associated with ALS and mutations in these genes account for more than a half of all familial cases and about 10% of sporadic cases. One of the most prevalent genes is TARDBP, responsible for approximately 4-6% of FALS and nearly 1-2% of SALS cases. The aim of this study was to perform the screening of known ALS genes, to increase the knowledge of the mutations that circulate in the population from Rio de Janeiro. Methods: The screening of mutations was performed through the Illumina Next Generation Sequencing (NGS) platform with the use of a sequencing panel that contained the TARDBP, SOD1, FUS, VAPB, SMN1 and SMN2 genes. Results: A novel missense mutation (p.Phe194Leu) in exon 5 of the TARDBP gene was found in a sporadic male patient who died at the age of 58 (2018). The mutation, a TTT/CTT substitution, was not detected in any mutation databases and in the literature. In silico analysis of this variant with different algorithms were performed and the results pointed to a probably damaging impact and that the mutation is disease causing. Conclusion: Through the study of the ALS genes by the NGS, we were able to identify a novel TARDBP mutation in a non-familial ALS patient. In addition, this study also increases the number of known TARDBP mutations in ALS patients and our knowledge of the mutations that affect the patients from of population from Rio de Janeiro.