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

Abstract

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.

• Authors: Hannah M Kaneb, Andrew W Folkmann, Véronique V Belzil, Li-En Jao, Claire S Leblond, Simon L Girard, Hussein Daoud, Anne Noreau, Daniel Rochefort, Pascale Hince, Anna Szuto, Annie Levert, Sabrina Vidal, Catherine André-Guimont, William Camu, Jean-Pierre Bouchard, Nicolas Dupré, Guy A Rouleau, Susan R Wente, Patrick A Dion
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 5 Pg. 1363-73 (Mar 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25343993 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Codon, Nonsense
• DNA-Binding Proteins
• Gle1 protein, human
• Nucleocytoplasmic Transport Proteins
• RNA, Messenger

Topics

• Amyotrophic Lateral Sclerosis (genetics, pathology)
• Animals
• Arthrogryposis (genetics)
• Codon, Nonsense
• DNA-Binding Proteins (genetics, metabolism)
• Disease Models, Animal
• Haploinsufficiency (genetics)
• HeLa Cells
• Humans
• Microscopy, Confocal
• Motor Neurons (pathology)
• Mutation, Missense
• Nuclear Pore (genetics, metabolism)
• Nucleocytoplasmic Transport Proteins (genetics, metabolism)
• Pedigree
• Protein Processing, Post-Translational
• RNA Splicing
• RNA, Messenger (metabolism)
• Zebrafish