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

Nousiainen, Heidi; Kestilä, Marjo; Pakkasjärvi, Niklas; Honkala, Heli; Kuure, Satu; Tallila, Jonna; Vuopala, Katri; Ignatius, Jaakko; Herva, Riitta; Peltonen, Leena

doi:10.1038/ng.2007.65

Cited by 185 publications

(193 citation statements)

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“…Mutations in various RNA-binding proteins, such as SMN, TARDBP, FUS and GLE1 have been identified as genetic causes of motor neuron degeneration (Lefebvre et al, 1995, Sreedharan et al, 2008, Nousiainen et al, 2008, Vance et al, 2009. The GLE1 gene is mutated in LCCS1, a severe autosomal recessive fetal motor neuron disease (Nousiainen et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

“…Other symptoms include hypolasia, pytergia, multiple joint contractures and micrognathia. Prenatal death usually occurs before the 32 nd gestation week (Nousiainen et al, 2008 ). More recently, it has been suggested that haploinsufficieny for GLE1 may be a genetic factor predisposing to ALS (Kaneb et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…GLE1-002 mRNA, which produces the 698 amino acid GLE1B peptide, is reported to be expressed about a thousand times more than the GLE1-001 mRNA encoding GLE1A in HeLa cells and its product dominates the intracellular localization profile (Kendirgi et al, 2003). The GLE1 protein has nuclear pore complex (NPC) targeting, coiled-coil, nuclear shuttling and nuclear rim targeting domains (Rayala et al, 2004, Kendirgi et al, 2005, Nousiainen et al, 2008. It 4 has been shown to have several essential roles in vital cellular processes such as mRNA export, translation initiation and translation termination.…”

Section: Introductionmentioning

confidence: 99%

“…The GLE1 gene is mutated in LCCS1, a severe autosomal recessive fetal motor neuron disease (Nousiainen et al, 2008 ). The disease is characterized by total immobility of the fetus, which can be detected around the 13 th week of gestation (Nousiainen et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

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Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

et al. 2016

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-GLE1 mutations cause lethal congenital contracture syndrome 1 (LCCS1), a severe autosomal recessive fetal motor neuron disease, and more recently have been associated with amyotrophic lateral sclerosis (ALS). The gene encodes a highly conserved protein with an essential role in mRNA export. The mechanism linking Gle1 function to motor neuron degeneration in humans has not been elucidated, but increasing evidence implicates abnormal RNA processing as a key event in the pathogenesis of several motor neuron

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

et al. 2016

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“…For example, in patients with osteogenesis imperfecta type I, a splice site mutation causes the entrapment of the COL1A1 (collagen type 1, alpha 1) pre-mRNA in the nucleus, which prevents translation in the cytoplasm (Johnson et al, 2000). Moreover, mutations in the mRNA export factor GLE1 are responsible for motor neuron diseases, LCCS1 (lethal congenital contracture syndrome 1) and LAAHD (lethal arthrogryposis with anterior horn cell disease) (Nousiainen et al, 2008).…”

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confidence: 99%

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

Mastroyiannopoulos

Shammas

Phylactou

2010

Biology of the Cell

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Cyprus DM1 (myotonic dystrophy type I) is a common form of muscular dystrophy that affects mainly adults. It is a disease that belongs to the group of defective RNA export diseases, since a major part of the pathogenic mechanism of the disease is the retention of the mutant transcripts in the cell nucleus. The presence of an expanded CUG trinucleotide repeat in the 3 -UTR (3 -untranslated region) of the DMPK (myotonic dystrophy protein kinase) gene causes the attraction of RNA-binding proteins by the nuclear-located mutant transcripts. As a result of the occupation of the RNA-binding proteins, there is defective mis-splicing of several cellular transcripts. This is believed to be a major pathogenic mechanism of the disease and any attempt to repair the activities of the RNA-binding proteins or target the mutant transcripts should be beneficial for the patients. Certain approaches have been described in the literature and they demonstrate progress in various directions. The purpose of the present review is to summarize the successful attempts to tackle the pathogenesis caused by nuclear retention of mutant transcripts in myotonic dystrophy and to discuss the possible gains from such approaches.

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TDP‐43 and FUS en route from the nucleus to the cytoplasm

Ederle¹,

2017

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Misfolded or mislocalized RNA‐binding proteins (RBPs) and, consequently, altered mRNA processing, can cause neuronal dysfunction, eventually leading to neurodegeneration. Two prominent examples are the RBPs TAR DNA‐binding protein of 43 kDa (TDP‐43) and fused in sarcoma (FUS), which form pathological messenger ribonucleoprotein aggregates in patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative disorders. Here, we review the multiple functions of TDP‐43 and FUS in mRNA processing, both in the nucleus and in the cytoplasm. We discuss how TDP‐43 and FUS may exit the nucleus and how defects in both nuclear and cytosolic mRNA processing events, and possibly nuclear export defects, may contribute to neurodegeneration and ALS/FTD pathogenesis.

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

Cited by 185 publications

References 15 publications

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

TDP‐43 and FUS en route from the nucleus to the cytoplasm

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