Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts

ARPP21 has recently emerged as a new amyotrophic lateral sclerosis (ALS) associated gene but its pathogenic role remains unclear. In this study we performed familial, clinical, neuropathological and cellular analyses to characterize the recurrent p.P529L and p.P713L variants (also known as p.P563L variant and p.P747L variant, respectively) in our French ALS cohort of 1190 ALS cases and 50 additional family members available for segregation analysis, resulting in the description of 29 ARPP21-linked patients. ARPP21 emerged as the most frequent rare ALS-associated gene in France after exclusion of the four major ALS genes, accounting for 2.7% of familial cases (fALS) and 0.1% of sporadic cases. Age-dependent penetrance reached 45% by age 50 and increased only modestly thereafter, remaining incomplete even at advanced ages. In cellular models, the p.P713L mutant showed aggregation associated with protein hyperphosphorylation and colocalization with the autophagic marker p62. Neuropathological examination of tissue from a p.P529L carrier revealed typical cytoplasmic TDP-43 pathology, together with heterogeneous ARPP21-positive deposits. As ARPP21 antibody also stained granulovacuolar degenerations, ARPP21-positive deposits may reflect neuronal stress rather than mutant ARPP21-specific pathology. Nevertheless, together with previous studies, our findings support ARPP21 as an important ALS-associated gene, and indicate that both p.P529L/p.P563L and p.P713L/p.P747L should be considered pathogenic ALS-causing variants. Incorporating ARPP21 into the routine genetic testing panels for fALS could improve diagnostic yield.

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Journal
Acta Neuropathologica
Published
2026-09-04
DOI
https://doi.org/10.1007/s00401-026-03075-6
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts

Béatrice Lannes, Susana Boluda, Stéphanie Millecamps, Claire Guissart et al.
Acta Neuropathologica
Amyotrophic Lateral Sclerosis Research
article

Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts

Béatrice Lannes, Susana Boluda, Stéphanie Millecamps, Claire Guissart, Anna‐Gaëlle Giguet‐Valard, E Bernard, Elisa De la Cruz, Tomoko Miki, Mathilde Duchesne, Christophe Vial, Franck Letournel, Romain Perbet, Anne‐Laure Fauret‐Amsellem, Katell Beauvais, Valérie Rigau, F. Paysant, Isabelle Plu, David Meyronnet, Jean Boutonnat, Séverine Boillée, Adrien Bohic, Florence Esselin, Maxime Faisant, Dan Christian Chiforeanu, Rémi Bellance, Sibylle De Bertier, Maria-Del-Mar Amador, Christian S. Lobsiger, Danielle Seilhean, Brainbank Neuro-CEB Neuropathology Network, Marie-Laure Martin-Négrier, Vincent Deramecourt, Clémence Delteil, Delphine Bohl, William Camu, Florent Marguet, François Salachas, Virginie Scolandre, Claude-Alain Maurage, Laurianne Geoffray, Catherine Godfraind, Vincent Meininger, Gaelle Bruneteau
article en

Abstract

ARPP21 has recently emerged as a new amyotrophic lateral sclerosis (ALS) associated gene but its pathogenic role remains unclear. In this study we performed familial, clinical, neuropathological and cellular analyses to characterize the recurrent p.P529L and p.P713L variants (also known as p.P563L variant and p.P747L variant, respectively) in our French ALS cohort of 1190 ALS cases and 50 additional family members available for segregation analysis, resulting in the description of 29 ARPP21-linked patients. ARPP21 emerged as the most frequent rare ALS-associated gene in France after exclusion of the four major ALS genes, accounting for 2.7% of familial cases (fALS) and 0.1% of sporadic cases. Age-dependent penetrance reached 45% by age 50 and increased only modestly thereafter, remaining incomplete even at advanced ages. In cellular models, the p.P713L mutant showed aggregation associated with protein hyperphosphorylation and colocalization with the autophagic marker p62. Neuropathological examination of tissue from a p.P529L carrier revealed typical cytoplasmic TDP-43 pathology, together with heterogeneous ARPP21-positive deposits. As ARPP21 antibody also stained granulovacuolar degenerations, ARPP21-positive deposits may reflect neuronal stress rather than mutant ARPP21-specific pathology. Nevertheless, together with previous studies, our findings support ARPP21 as an important ALS-associated gene, and indicate that both p.P529L/p.P563L and p.P713L/p.P747L should be considered pathogenic ALS-causing variants. Incorporating ARPP21 into the routine genetic testing panels for fALS could improve diagnostic yield.

Acta NeuropathologicaVol. 152(1)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Sorbonne Université (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre Hospitalier Universitaire de Nîmes (FR), Hôpital Pierre Wertheimer (FR), Hôpital Gui de Chauliac (FR), CHU Dijon Bourgogne (FR), Pitié-Salpêtrière Hospital (FR), Institute for Neurosciences of Montpellier (FR), Centre Hospitalier Universitaire de Martinique (MQ), Institut du Cerveau (FR), Générale de Santé (FR), Université de Nîmes (FR)
Fondation Vaincre Alzheimer, Association de soutien à la Paralysie Supranucléaire Progressive, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, China Scholarship Council, Centre Hospitalier Régional Universitaire de Montpellier, Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone, Association France Parkinson, Centre Hospitalier Universitaire de Rennes
Reduced inequalities
Openalex Percentile: Top 11%
Amyotrophic Lateral Sclerosis Research
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