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

作者：Kaneb Hannah M; Folkmann Andrew W; Belzil Veronique V; Jao Li En; Leblond Claire S; Girard Simon L; Daoud Hussein; Noreau Anne; Rochefort Daniel; Hince Pascale; Szuto Anna; Levert Annie; Vidal Sabrina; Andre Guimont Catherine; Camu William; Bouchard Jean Pierre; Dupre Nicolas; Rouleau Guy A; Wente Susan R; Dion Patrick A^*

来源：Human Molecular Genetics, 2015, 24(5): 1363-1373.

DOI：10.1093/hmg/ddu545

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.

• 出版日期2015-3-1
• 单位McGill