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Hum Mol Genet. 2015 Mar 1;24(5):1363-73. doi: 10.1093/hmg/ddu545. Epub 2014 Oct 24.

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

Author information

1
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.
2
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
3
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.
4
Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada H3A 2B4, Department of Human Genetics, McGill University, Montreal, QC, Canada H3A 0G4.
5
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.
6
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.
7
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.
8
Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada H3A 2B4.
9
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, QC, Canada H2L 2W5.
10
Department of Biochemistry, Université de Montréal.
11
Department of Biological Sciences, Université de Montréal, Montréal, QC, Canada H2L 4M1.
12
Unité de Neurologie Comportementale et Dégénérative, Institute of Biology, Montpellier 34967, France.
13
Department of Neurological Sciences and Faculty of Medicine, Centre Hospitalier Universitaire de Québec, Laval University, Quebec City, QC, Canada G1J 1Z4.
14
Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada H3A 2B4, Department of Neurology and Neurosurgery, McGill University.
15
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.

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.

PMID:
25343993
PMCID:
PMC4321443
DOI:
10.1093/hmg/ddu545
[Indexed for MEDLINE]
Free PMC Article

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