• J. Neurol. Neurosurg. Psychiatr. · Jul 2024

    Identification of a pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis.

    • Oriol Dols-Icardo, Álvaro Carbayo, Ivonne Jericó, Olga Blasco-Martínez, Esther Álvarez-Sánchez, Maria Angeles López Pérez, Sara Bernal, Benjamín Rodríguez-Santiago, Ivon Cusco, Janina Turon-Sans, Manuel Cabezas-Torres, Marta Caballero-Ávila, Ana Vesperinas, Laura Llansó, Inmaculada Pagola-Lorz, Laura Torné, Natalia Valle-Tamayo, Laia Muñoz, Sara Rubio-Guerra, Ignacio Illán-Gala, Elena Cortés-Vicente, Ellen Gelpi, and Ricard Rojas-García.
    • Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain rrojas@santpau.cat odols@santpau.cat.
    • J. Neurol. Neurosurg. Psychiatr. 2024 Jul 2.

    Background And ObjectiveBetween 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.MethodsWe 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.ResultsWe identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) 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.ConclusionsWhile previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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