Deleterious mutations in the essential mRNA metabolism factor, hGle1, in Amyotrophic Lateral Sclerosis

ALS is a fatal neurodegenerative disorder characterised by the selective death of motor neurons. Causative mutations in the global RNA processing proteins TDP-43 and FUS amongst others, as well as their aggregation in ALS patients have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn cell disease (LAAHD) are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified two deleterious mutations (one splice site and one nonsense mutation) and a missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.