title: 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.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada H3A 2B4, Department of Neurology and Neurosurgery, McGill University, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC, Canada H2L 2W5.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Kaneb
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Folkmann
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC, Canada H2L 2W5, Department of Physiology, Université de Montréal.
authors.forename: Véronique V
authors.initials: VV
authors.lastname: Belzil
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Li-En
authors.initials: LE
authors.lastname: Jao
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada H3A 2B4, Department of Human Genetics, McGill University, Montreal, QC, Canada H3A 0G4.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Leblond
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC, Canada H2L 2W5, Department of Molecular Biology, Université de Montréal.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Girard
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC, Canada H2L 2W5, Department of Medicine, Université de Montréal.
authors.forename: Hussein
authors.initials: H
authors.lastname: Daoud
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC, Canada H2L 2W5, Department of Pathology and Cellular Biology, Université de Montréal.
authors.forename: Anne
authors.initials: A
authors.lastname: Noreau
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada H3A 2B4.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada H3A 2B4.
authors.forename: Pascale
authors.initials: P
authors.lastname: Hince
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC, Canada H2L 2W5.
authors.forename: Anna
authors.initials: A
authors.lastname: Szuto
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada H3A 2B4.
authors.forename: Annie
authors.initials: A
authors.lastname: Levert
authors.affiliation: Department of Biochemistry, Université de Montréal.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Vidal
authors.affiliation: Department of Biological Sciences, Université de Montréal, Montréal, QC, Canada H2L 4M1.
authors.forename: Catherine
authors.initials: C
authors.lastname: André-Guimont
authors.affiliation: Unité de Neurologie Comportementale et Dégénérative, Institute of Biology, Montpellier 34967, France.
authors.forename: William
authors.initials: W
authors.lastname: Camu
authors.affiliation: Department of Neurological Sciences and Faculty of Medicine, Centre Hospitalier Universitaire de Québec, Laval University, Quebec City, QC, Canada G1J 1Z4.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bouchard
authors.affiliation: Department of Neurological Sciences and Faculty of Medicine, Centre Hospitalier Universitaire de Québec, Laval University, Quebec City, QC, Canada G1J 1Z4.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupré
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada H3A 2B4, Department of Neurology and Neurosurgery, McGill University.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Wente
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada H3A 2B4, Department of Neurology and Neurosurgery, McGill University, Department of Pathology and Cellular Biology, Université de Montréal, patrick.a.dion@mcgill.ca.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001176:Arthrogryposis / Q000235:genetics; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D057895:Haploinsufficiency / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D009046:Motor Neurons / Q000473:pathology; D020125:Mutation, Missense; D022022:Nuclear Pore / Q000235:genetics / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011499:Protein Processing, Post-Translational; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D015027:Zebrafish
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C474082:Gle1 protein, human; D029543:Nucleocytoplasmic Transport Proteins; D012333:RNA, Messenger