Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated...

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.