Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways.

Molecular and Cellular Biology
Wei LiChristopher G Proud

Abstract

Leukoencephalopathy with vanishing white matter (VWM) is a severe inherited human neurodegenerative disorder that is caused by mutations in the genes for the subunits of eukaryotic initiation factor 2B (eIF2B), a heteropentameric guanine nucleotide exchange factor that regulates both global and mRNA-specific translation. Marked variability is evident in the clinical severity and time course of VWM in patients. Here we have studied the effects of VWM mutations on the function of human eIF2B. All the mutations tested cause partial loss of activity. Frameshift mutations in genes for eIF2Bepsilon or eIF2Bbeta lead to truncated polypeptides that fail to form complexes with the other subunits and are effectively null mutations. Certain point mutations also impair the ability of eIF2Bbeta or -epsilon to form eIF2B holocomplexes and also diminish the intrinsic nucleotide exchange activity of eIF2B. A point mutation in the catalytic domain of eIF2Bepsilon impairs its ability to bind the substrate, while two mutations in eIF2Bbeta actually enhance eIF2 binding. We provide evidence that expression of VWM mutant eIF2B may enhance the translation of specific mRNAs. The variability of the clinical phenotype in VWM may reflect the multiple wa...Continue Reading

References

Mar 1, 1994·Annals of Neurology·R SchiffmannC R Kaneski
Mar 27, 1996·Biochemical and Biophysical Research Communications·B L Craddock, C G Proud
Apr 1, 1997·Neurology·M S van der KnaapJ Valk
Aug 26, 1998·Neurology·M S van der KnaapJ Valk
Aug 12, 1999·American Journal of Human Genetics·P A LeegwaterM S van der Knaap
Jun 16, 2001·The Journal of Biological Chemistry·W LiC G Proud
Sep 29, 2001·Progress in Molecular and Subcellular Biology·M J Clemens
Sep 29, 2001·Progress in Molecular and Subcellular Biology·C G Proud
Sep 27, 2002·Annals of Neurology·Anne FogliRaphael Schiffmann
Apr 23, 2003·American Journal of Human Genetics·Anne FogliOdile Boespflug-Tanguy

❮ Previous
Next ❯

Citations

Jan 13, 2012·The Journal of Biological Chemistry·Xuemin WangChristopher G Proud
Sep 1, 2009·Assay and Drug Development Technologies·Nuzhat MotlekarAndrew D Napper
Nov 11, 2009·The Neurologist·Daniel J CostelloFlorian S Eichler
Sep 13, 2005·Annual Review of Microbiology·Alan G Hinnebusch
Nov 3, 2012·PloS One·Arup PandaTapash Chandra Ghosh
May 16, 2012·Advances in Nutrition·Thomas D Baird, Ronald C Wek
Sep 6, 2005·Journal of Neuropathology and Experimental Neurology·J Patrick van der VoornMarjo S van der Knaap
Sep 15, 2010·Journal of Neuropathology and Experimental Neurology·Marianna BugianiMarjo S van der Knaap
Nov 15, 2008·Lancet Neurology·Enza Maria ValenteBruno Dallapiccola
Oct 2, 2007·Pediatric Neurology·Florian Eichler, Keith Van Haren
Mar 31, 2009·Journal of Neuroscience Research·Maurizio D'AntonioLawrence Wrabetz
Mar 15, 2016·The Journal of Clinical Investigation·Stephanie DoovesMarjo S van der Knaap
Jan 22, 2005·Seminars in Cell & Developmental Biology·Christopher G Proud
Dec 9, 2014·Cell Cycle·Martin D Jennings, Graham D Pavitt
Jul 4, 2006·Pediatric Neurology·Vijay RamaswamyHanna K Kolski
Apr 25, 2006·Lancet Neurology·Marjo S van der KnaapGert C Scheper
Mar 21, 2006·Trends in Molecular Medicine·Gert C ScheperMarjo S van der Knaap
Sep 28, 2005·Neurobiology of Disease·Barbara van KollenburgGert C Scheper
Nov 26, 2011·The Biochemical Journal·Craig R PigottChristopher G Proud
Oct 14, 2014·Frontiers in Cellular Neuroscience·Cristian A DroppelmannMichael J Strong
Jul 9, 2010·PloS One·Kathleen Schwerdtner Máñez, Sebastian C A Ferse
Feb 12, 2008·Journal of Child Neurology·Jelena MaletkovicAdeline Vanderver
Jun 3, 2005·Nature·Claire Ainsworth
Jan 30, 2018·Frontiers in Cellular Neuroscience·Lisanne E WisseTruus E M Abbink
Jul 11, 2018·Wiley Interdisciplinary Reviews. RNA·Graham D Pavitt
Jun 30, 2006·Mental Retardation and Developmental Disabilities Research Reviews·Jan C PronkMarjo S van der Knaap

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.