ReviewC9orf72 isoforms in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

A hexanucleotide (G4C2) repeat expansion in the 5′ non-coding region C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Three modes of toxicity have been proposed: gain of function through formation of RNA foci and sequestration of RNA binding proteins; expression of dipeptide repeat proteins generated by repeat-associated non-ATG translation; and loss of function due to C9orf72 haploinsufficiency. Much is known about the proposed gain of function mechanisms, but there is little knowledge of the normal function of C9orf72 and the cellular consequences if its activity is perturbed. Here we will review what is known of C9orf72 at the transcript and protein levels and how changes in C9orf72 expression could contribute to disease pathogenesis.This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.