Since 2008, several groups have reported a lot of dominant mutations in TARDBP gene as a primary cause of Amyotrophic lateral sclerosis (ALS). Mutations in TARDBP gene are responsible for 4-5% of familial ALS (fALS) and nearly 1% of sporadic ALS (sALS). To date, over 50 dominant mutations were found in TDP-43 in both familial and sporadic ALS patients, most of which were missense mutations in the C-terminal glycine-rich region. Herein, we describe the clinical and genetic analysis of an Italian non-familial ALS patient with a late onset and a rapid disease progression, which led to the discovery of a novel TARDBP mutation. After neurological evaluation, molecular investigation highlighted the heterozygous substitution in exon 6 of TARDBP gene (S379A), which has previously neither been described nor reported in the ALS database. Several evidences supported the S379A mutation as causative in our patient: (a) it was neither found in ExAC nor 1000G and it was absent in our database of control subjects; (b) the position of the mutation involves an evolutionarily highly conserved residue; (c) two different amino acid substitutions in the same 379 codon were already reported in Swedish and Italian fALS cases, supporting the critical role of this codon for the protein function. The identification of this novel mutation enlarges the number of TARDBP mutations in ALS patients.

A novel S379A TARDBP mutation associated to late-onset sporadic ALS

Naimo, Giuseppina Daniela;Conforti, Francesca Luisa
2019

Abstract

Since 2008, several groups have reported a lot of dominant mutations in TARDBP gene as a primary cause of Amyotrophic lateral sclerosis (ALS). Mutations in TARDBP gene are responsible for 4-5% of familial ALS (fALS) and nearly 1% of sporadic ALS (sALS). To date, over 50 dominant mutations were found in TDP-43 in both familial and sporadic ALS patients, most of which were missense mutations in the C-terminal glycine-rich region. Herein, we describe the clinical and genetic analysis of an Italian non-familial ALS patient with a late onset and a rapid disease progression, which led to the discovery of a novel TARDBP mutation. After neurological evaluation, molecular investigation highlighted the heterozygous substitution in exon 6 of TARDBP gene (S379A), which has previously neither been described nor reported in the ALS database. Several evidences supported the S379A mutation as causative in our patient: (a) it was neither found in ExAC nor 1000G and it was absent in our database of control subjects; (b) the position of the mutation involves an evolutionarily highly conserved residue; (c) two different amino acid substitutions in the same 379 codon were already reported in Swedish and Italian fALS cases, supporting the critical role of this codon for the protein function. The identification of this novel mutation enlarges the number of TARDBP mutations in ALS patients.
ALS; Mutation; TARDBP; TDP-43
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11770/294438
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