Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease - PubMed (original) (raw)

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

Heidi O Nousiainen et al. Nat Genet. 2008 Feb.

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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Figures

Figure 1

Figure 1

A 23-week-old LCCS1 fetus with typical malpositioning of limbs and severe micrognathia.

Figure 2

Figure 2

Detailed structure of the GLE1 gene and GLE1b protein, with identified mutations and predicted effects on the polypeptide. GLE1, comprising 16 exons, encodes a protein (GLE1b) with several functional domains. The mutations identified in LCCS1 and LAAHD cases affect the coiled-coil domain of GLE1b, as well as the C-terminal region, which contains the CG1-binding domain. Schematic modified from those previously reported,.

Figure 3

Figure 3

The disease genes underlying LCCS2 and LCCS3 encode members of the phosphatidyl inositol pathway involved in the synthesis of inositol hexakisphosphate. In budding yeast, inositol hexakisphosphate and Gle1 are both required to activate the Dbp5 protein for mRNA export.

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