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Molecular and Cellular Biology, April 2004, p. 3295-3306, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3295-3306.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mutations Linked to Leukoencephalopathy with Vanishing White Matter Impair the Function of the Eukaryotic Initiation Factor 2B Complex in Diverse Ways

Wei Li,^1, Xuemin Wang,^1, Marjo S. van der Knaap,² and Christopher G. Proud^1,*

Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom,¹ Department of Child Neurology, Free University Medical Center, Amsterdam, The Netherlands²

Received 8 September 2003/ Returned for modification 14 November 2003/ Accepted 14 January 2004

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 eIF2B or eIF2Bß 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 eIF2Bß or - to form eIF2B holocomplexes and also diminish the intrinsic nucleotide exchange activity of eIF2B. A point mutation in the catalytic domain of eIF2B impairs its ability to bind the substrate, while two mutations in eIF2Bß 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 ways in which VWM mutations affect eIF2B function.

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* Corresponding author. Mailing address: Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom. Phone: 44 1382 344919. Fax: 44 1382 345507. E-mail: c.g.proud{at}dundee.ac.uk.

W.L. and X.W. should be considered joint first authors.

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Molecular and Cellular Biology, April 2004, p. 3295-3306, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3295-3306.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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