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

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

Research output: Contribution to journalArticle

77 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1363-1373
Number of pages11
JournalHuman Molecular Genetics
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

Fingerprint

Amyotrophic Lateral Sclerosis
Messenger RNA
Mutation
RNA
Motor Neurons
Nuclear Pore
Haploinsufficiency
Motor Neuron Disease
Cell Nucleus Active Transport
Nonsense Codon
Zebrafish
Missense Mutation
HeLa Cells
Neurodegenerative Diseases
Proteins
Pathology

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kaneb, H. M., Folkmann, A. W., Belzil, V. V., Jao, L-E., Leblond, C. S., Girard, S. L., ... Dion, P. A. (2015). Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Human Molecular Genetics, 24(5), 1363-1373. https://doi.org/10.1093/hmg/ddu545

Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. / Kaneb, Hannah M.; Folkmann, Andrew W.; Belzil, Véronique V.; Jao, Li-En; Leblond, Claire S.; Girard, Simon L.; Daoud, Hussein; Noreau, Anne; Rochefort, Daniel; Hince, Pascale; Szuto, Anna; Levert, Annie; Vidal, Sabrina; André-Guimont, Catherine; Camu, William; Bouchard, Jean Pierre; Dupré, Nicolas; Rouleau, Guy A.; Wente, Susan R.; Dion, Patrick A.

In: Human Molecular Genetics, Vol. 24, No. 5, 01.03.2015, p. 1363-1373.

Research output: Contribution to journalArticle

Kaneb, 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, JP, Dupré, N, Rouleau, GA, Wente, SR & Dion, PA 2015, 'Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis', Human Molecular Genetics, vol. 24, no. 5, pp. 1363-1373. https://doi.org/10.1093/hmg/ddu545
Kaneb, Hannah M. ; Folkmann, Andrew W. ; Belzil, Véronique V. ; Jao, Li-En ; Leblond, Claire S. ; Girard, Simon L. ; Daoud, Hussein ; Noreau, Anne ; Rochefort, Daniel ; Hince, Pascale ; Szuto, Anna ; Levert, Annie ; Vidal, Sabrina ; André-Guimont, Catherine ; Camu, William ; Bouchard, Jean Pierre ; Dupré, Nicolas ; Rouleau, Guy A. ; Wente, Susan R. ; Dion, Patrick A. / Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 5. pp. 1363-1373.
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