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

82 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Kaneb, H. M., Folkmann, A. W., Belzil, V. V., Jao, L-E., Leblond, C. S., Girard, S. L., Daoud, H., Noreau, A., Rochefort, D., Hince, P., Szuto, A., Levert, A., Vidal, S., André-Guimont, C., Camu, W., Bouchard, J. P., Dupré, N., Rouleau, G. A., Wente, S. R., & 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