Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis.

TitleDeleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis.
Publication TypeJournal Article
Year of Publication2015
AuteursKaneb, HM, Folkmann, AW, Belzil, VV, Jao, L-E, Leblond, CS, Girard, SL, Daoud, H, Noreau, A, Rochefort, D, Hince, P, Szuto, A, Levert, A, Vidal, S, André-Guimont, C, Camu, W, Bouchard, J-P, Dupré, N, Rouleau, GA, Wente, SR, Dion, PA
JournalHum Mol Genet
Date Published2015 Mar 01
KeywordsAmyotrophic Lateral Sclerosis, Animals, Arthrogryposis, Codon, Nonsense, Disease Models, Animal, DNA-Binding Proteins, Haploinsufficiency, HeLa Cells, Humans, Microscopy, Confocal, Motor Neurons, Mutation, Missense, Nuclear Pore, Nucleocytoplasmic Transport Proteins, Pedigree, Protein Processing, Post-Translational, RNA Splicing, RNA, Messenger, Zebrafish

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among 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 and lethal arthrogryposis with anterior horn cell disease 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 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 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.

Alternate JournalHum. Mol. Genet.
PubMed ID25343993
PubMed Central IDPMC4321443
Grant ListT32 CA119925 / CA / NCI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R37 GM051219 / GM / NIGMS NIH HHS / United States
R37 GM51219 / GM / NIGMS NIH HHS / United States
NS070431 / NS / NINDS NIH HHS / United States