Journal of neurology, neurosurgery, and psychiatry · 2025
Identification of a pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis.
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Dols-Icardo Oriol, Carbayo Álvaro, Jericó Ivonne, Blasco-Martínez Olga, Álvarez-Sánchez Esther, López Pérez Maria Angeles, Bernal Sara, Rodríguez-Santiago Benjamín, Cusco Ivon, Turon-Sans Janina, Cabezas-Torres Manuel, Caballero-Ávila Marta, Vesperinas Ana, Llansó Laura, Pagola-Lorz Inmaculada, Torné Laura, Valle-Tamayo Natalia, Muñoz Laia, Rubio-Guerra Sara, Illán-Gala Ignacio, Cortés-Vicente Elena, Gelpi Ellen, Rojas-García Ricard
Аннотация
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.
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.