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

Background and objective 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...

Full description

Bibliographic Details
Authors: Dols-Icardo, O, Carbayo, A, Jericó, I, Blasco-Martínez, O, Alvarez-Sánchez, E, Pérez, MAL, Bernal, S, Rodríguez-Santiago, B, Cusco, I, Turon-Sans, J, Cabezas-Torres, M, Caballero-Avila, M, Vesperinas, A, Llansó, L, Pagola-Lorz, I, Torné, L, Valle-Tamayo, N, Muñoz, L, Rubio-Guerra, S, Illán-Gala, I, Cortés-Vicente, E, Gelpi, E, Rojas-García, R
Format: article
Status:Published version
Publication Date:2025
Country:España
Institution:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repository:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p17938
Online Access:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=17938
Access Level:Open access
Keyword:ALS
MOTOR NEURON DISEASE
GENETICS
FRONTOTEMPORAL DEMENTIA
EPIDEMIOLOGY
Description
Summary:Background and objective 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. Methods 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. Results We 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. Conclusions While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.

Similar Items