Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis

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.

Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2

“…Interestingly, mutations in the RNA export gene hGle1 cause fetal motor neuron disease and have recently been associated with ALS [8], while loss of several components of the RNA transcription and export complex (TREX) suppress TDP-43 toxicity in yeast [45]. We therefore sought to determine whether other components of the RNA export machinery are involved in mediating TDP-43 toxicity in Drosophila .…”

“…We report the identification of three genes that suppress TDP-43 toxicity, including Shaggy/GSK3 , a known modifier of neurodegeneration [6]. The two additional novel suppressors, Hat-trick and Xmas-2 , function in chromatin modeling and RNA export, two processes recently implicated in human ALS [7, 8]. Loss of Shaggy/GSK3 , Hat-trick or Xmas-2 does not suppress Wallerian degeneration, arguing TDP-43 Q331K -induced and Wallerian degeneration are genetically distinct processes.…”

Control of mammalian gene expression by selective mRNA export

“…Mutations in another mRNA export factor have also been implicated in autosomal recessive motor neuron disease 135 and in amyotrophic lateral sclerosis (ALS) 136 . Mutations in GLE1 are responsible for lethal congenital contracture syndrome 1 (LCCS1) 135 .…”

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

“…32,33 For example, mutations in the human mRNA-export mediator GLE1 (MIM: 603371) result in a severe fetal motor neuron disease 34 (lethal congenital contracture syndrome 1 [MIM: 253310]) and amyotrophic lateral sclerosis. 35 Impaired RNA transport out of the nucleus can be caused by a splice-site mutation in COL1A1 (MIM: 120150) in some affected individuals with osteogenesis imperfect, type I 36 (MIM: 166200). Impaired RNA transport out of the nucleus can also be caused by toxic CUG expansion in the 3 0 UTR of the dystrophia myotonica-protein kinase mRNA in individuals affected by myotonic dystrophy 1 (MIM: 160900).…”