Pathogenic mutation in ARPP21 in patients with amyotrophic lateral sclerosis

 

http://orcid.org/0000-0003-2656-8748Oriol Dols-Icardo1,2, 

http://orcid.org/0000-0001-9282-8603Álvaro Carbayo3,4,5, 

Ivonne Jericó6,7, 

Olga Blasco-Martínez8, 

Esther Álvarez-Sánchez1,2, 

Maria Angeles López Pérez8, 

Sara Bernal4,9, 

Benjamín Rodríguez-Santiago4,9,10, 

Ivon Cusco9, 

Janina Turon-Sans3,4,5, 

Manuel Cabezas-Torres3,4, 

http://orcid.org/0000-0001-9850-8504Marta Caballero-Ávila3,4,5, 

Ana Vesperinas3,4,5, 

Laura Llansó3,4,5, 

Inmaculada Pagola-Lorz6,7, 

Laura Torné6,7, 

Natalia Valle-Tamayo1,2, 

Laia Muñoz1,2, 

http://orcid.org/0000-0001-7652-8029Sara Rubio-Guerra1,2, 

http://orcid.org/0000-0002-5418-2052Ignacio Illán-Gala1,2, 

http://orcid.org/0000-0002-1428-1072Elena Cortés-Vicente3,4,5, 

Ellen Gelpi11, 

http://orcid.org/0000-0003-1411-5573Ricard Rojas-García3,4,5

1. Correspondence to Dr Ricard Rojas-García, Neurology, Hospital de la Santa Creu i Sant Pau, Unidad de Enfermedades Neuromusculares, Barcelona, Spain; rrojas@santpau.cat; Dr Oriol Dols-Icardo; odols@santpau.cat

2. Abstract

   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.

3. https://jnnp.bmj.com/content/early/2024/07/02/jnnp-2024-333834