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Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease

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.

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Figure 1
Figure 2: Detailed structure of the GLE1 gene and GLE1b protein, with identified mutations and predicted effects on the polypeptide.
Figure 3: The disease genes underlying LCCS2 and LCCS3 encode members of the phosphatidyl inositol pathway involved in the synthesis of inositol hexakisphosphate.

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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.

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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.

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Correspondence to Marjo Kestilä.

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Supplementary Methods, Supplementary Tables 1–4, Supplementary Figures 1–3 (PDF 2861 kb)

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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

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