Identification of a pathogenic mutation in <i>ARPP21</i> in patients with amyotrophic lateral sclerosis.

Abstract

Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing. We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region. We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (<i>ARPP21)</i> gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes. While previous studies have dismissed a causal role of <i>ARPP21</i> in ALS, our results strongly support <i>ARPP21</i> as a novel ALS-causing gene.