Reconsidering the causality of TIA1 mutations in ALS

Abstract

T-cell-restricted intracellular antigen-1 (TIA1) has been recently reported as a novel amyotrophic lateral sclerosis (ALS) related gene, and has already been adopted in a resource frequently used in the clinic (Neuromuscular Disease Center). The Project MinE Consortium has reviewed the data that support this inclusion, and suggest that the inclusion of this gene as causative is premature. Although the biology of TIA1 is very appealing and the published functional experiments have been well-performed, it is also the case that current guidelines stipulate that experimental data must be interpreted with clinical caution, as they do not always prove causality. Here, we argue that data from the published pedigree that supports TIA1 is insufficient to prove causality. We hold that burden analysis lacks crucial methodological details, and is therefore potentially flawed. Because of this, without a replication effort, we hold that rare TIA1 mutations cannot be regarded as causal in ALS, and that it is premature to include this gene in diagnostic panels for ALS and FTD.