Abstract
The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy of spinal cord motoneurons and fetal immobility. Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1. Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated in LCCS1, LCCS2 and LCCS3 and elucidates mRNA processing as a critical molecular mechanism in motoneuron development and maturation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Mäkelä-Bengs, P. et al. Am. J. Hum. Genet. 63, 506–516 (1998).
Herva, R., Conradi, N.G., Kalimo, H., Leisti, J. & Sourander, P. Am. J. Med. Genet. 29, 67–76 (1988).
Vuopala, K., Ignatius, J. & Herva, R. Hum. Pathol. 26, 12–19 (1995).
Rayala, H.J., Kendirgi, F., Barry, D.M., Majerus, P.W. & Wente, S.R. Mol. Cell. Proteomics 3, 145–155 (2004).
Kendirgi, F., Barry, D.M., Griffis, E.R., Powers, M.A. & Wente, S.R. J. Cell Biol. 160, 1029–1040 (2003).
Kendirgi, F., Rexer, D.J., Alcazar-Roman, A.R., Onishko, H.M. & Wente, S.R. Mol. Biol. Cell 16, 4304–4315 (2005).
Dubowitz, V. Eur. J. Paediatr. Neurol. 3, 49–51 (1999).
Briscoe, J. & Ericson, J. Curr. Opin. Neurobiol. 11, 43–49 (2001).
Pakkasjärvi, N. et al. J. Neurobiol. 65, 269–281 (2005).
Watkins, J.L., Murphy, R., Emtage, J.L. & Wente, S.R. Proc. Natl. Acad. Sci. USA 95, 6779–6784 (1998).
Narkis, G. et al. Am. J. Hum. Genet. 81, 589–595 (2007).
Narkis, G. et al. Am. J. Hum. Genet. 81, 530–539 (2007).
Weirich, C.S. et al. Nat. Cell Biol. 8, 668–676 (2006).
Alcazar-Roman, A.R., Tran, E.J., Guo, S. & Wente, S.R. Nat. Cell Biol. 8, 711–716 (2006).
Wang, W., van Niekerk, E., Willis, D.E. & Twiss, J.L. Dev. Neurobiol. 67, 1166–1182 (2007).
Acknowledgements
We thank the families for participating in the study, clinicians and genetic counselors for the sample collection and R. Timonen, K. Hautaviita and L. Kananen for technical help. The work was supported by the Center of Excellence of Disease Genetics of the Academy of Finland (grants 64334 and 202887) to L.P. by the Academy of Finland grants 211124 and 118468 to M.K. by the US National Institutes of Health grant PO1 ES11253-03 (L.P.), by the Biocentrum Helsinki Foundation (L.P.), by the Sigrid Juselius Foundation (M.K.) and by the Oulu University Hospital EVO grants to R.H.
Author information
Authors and Affiliations
Contributions
L.P. designed this study; M.K. and L.P. supervised this study; L.P., M.K. and R.H. obtained funding; M.K. and N.P. provided microsatellite marker analyses; H.O.N. and N.P. sequenced the candidate genes and analyzed sequences; H.O.N. and M.K. provided bioinformatics analysis; H.H. and S.K. provided in situ hybridization; J.T. and H.O.N provided functional studies; K.V., J.I. and R.H. performed phenotype assessment and sample collection; H.O.N. drafted the manuscript and H.O.N., M.K., N.P., J.I., R.H. and L.P. contributed to the writing of this paper.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Methods, Supplementary Tables 1–4, Supplementary Figures 1–3 (PDF 2861 kb)
Rights and permissions
About this article
Cite this article
Nousiainen, H., Kestilä, M., Pakkasjärvi, N. et al. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet 40, 155–157 (2008). https://doi.org/10.1038/ng.2007.65
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.2007.65
This article is cited by
-
Global carrier frequency and predicted genetic prevalence of patients with pathogenic sequence variants in autosomal recessive genetic neuromuscular diseases
Scientific Reports (2024)
-
Proteomic Profiles and Protein Network Analysis of Primary Human Leukocytes Revealed Possible Clearance Biomarkers for Staphylococcus aureus Infection
Current Microbiology (2023)
-
Exploring the lncRNA localization landscape within the retinal pigment epithelium under normal and stress conditions
BMC Genomics (2022)
-
Nuclear pore complexes — a doorway to neural injury in neurodegeneration
Nature Reviews Neurology (2022)
-
Nuclear Pore Dysfunction in Neurodegeneration
Neurotherapeutics (2022)