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

ARPP21

Aggregation of the p.P713L mutant with protein hyperphosphorylation and colocalization with the autophagy marker p62; typical cytoplasmic TDP-43 pathology in a p.P529L carrier

In a French cohort of 1,190 patients with amyotrophic lateral sclerosis, complemented by 50 additional family members available for segregation analysis, the authors characterized the recurrent ARPP21 p.P529L and p.P713L variants and described 29 carriers. Once the four major genes are excluded, ARPP21 becomes the most frequent rare disease-associated gene in France, accounting for 2.7% of familial 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 aggregated with protein hyperphosphorylation and colocalization with the autophagy marker p62, and neuropathological examination of a p.P529L carrier showed typical cytoplasmic TDP-43 pathology together with heterogeneous ARPP21-positive deposits. The authors note these deposits may reflect neuronal stress rather than mutant-specific pathology.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The figure that matters is 2.7% of familial cases: this places ARPP21 ahead of many genes already tested in routine practice and makes it directly useful when interpreting an unsolved familial amyotrophic lateral sclerosis exome. The 45% penetrance by age 50 must, however, be stated as such in predictive counselling, since it changes the conversation entirely compared with a highly penetrant gene. The authors' caveat about the specificity of ARPP21-positive deposits is honest and worth relaying: the neuropathological evidence remains indirect.

Analysis by Dr Thibaut Benquey