Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts
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.
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BibTeX
@article{bertier2026familial,
title = {{Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts}},
author = {Sibylle de Bertier and Maria-Del-Mar Amador and Claire Guissart and Tomoko Miki and Séverine Boillée and Christian S Lobsiger and Delphine Bohl and Anne-Laure Fauret-Amsellem and Adrien Bohic and Anna-Gaelle Giguet-Valard and Rémi Bellance and Katell Beauvais and Vincent Meininger and Gaelle Bruneteau and François Salachas and Christophe Vial and William Camu and Florence Esselin and Elisa de la Cruz and Emilien Bernard and Danielle Seilhean and Stéphanie Millecamps},
journal = {Acta Neuropathologica},
year = {2026},
month = sep,
doi = {10.1007/s00401-026-03075-6},
url = {https://hal.science/hal-05743867v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts
AU - Sibylle de Bertier
AU - Maria-Del-Mar Amador
AU - Claire Guissart
AU - Tomoko Miki
AU - Séverine Boillée
AU - Christian S Lobsiger
AU - Delphine Bohl
AU - Anne-Laure Fauret-Amsellem
AU - Adrien Bohic
AU - Anna-Gaelle Giguet-Valard
AU - Rémi Bellance
AU - Katell Beauvais
AU - Vincent Meininger
AU - Gaelle Bruneteau
AU - François Salachas
AU - Christophe Vial
AU - William Camu
AU - Florence Esselin
AU - Elisa de la Cruz
AU - Emilien Bernard
AU - Danielle Seilhean
AU - Stéphanie Millecamps
PY - 2026
DA - 2026/09/04
JO - Acta Neuropathologica
DO - 10.1007/s00401-026-03075-6
UR - https://hal.science/hal-05743867v1
AB - 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.
SN - 0001-6322
SN - 1432-0533
ER -