Characterization of the Properties of a Novel Mutation in VAPB in Familial Amyotrophic Lateral Sclerosis

Han-Jou Chen, Georgia Anagnostou, Andrea Chai, James Withers, Alex Morris, Jason Adhikaree, Giuseppa Pennetta, Jackie S. de Belleroche

Research output: Contribution to journalArticlepeer-review


Following the mutation screening of genes known to cause amyotrophic lateral sclerosis (ALS) in index cases from 107 familial ALS (FALS) kindred, a point mutation was identified in vesicle-associated membrane protein-associated protein B (VAPB), or VAMP-associated protein B, causing an amino acid change from threonine to isoleucine at codon 46 (T46I) in one FALS case but not in 257 controls. This is an important finding because it is only the second mutation identified in this gene that causes ALS. In order to investigate the pathogenic effects of this mutation, we have used a motor neuron cell line and tissue-specific expression of the mutant protein in Drosophila. We provide substantial evidence for the pathogenic effects of this mutation in abolishing the effect of wild type VAPB in the unfolded protein response, promoting ubiquitin aggregate formation, and activating neuronal cell death. We also report that expression of the mutant protein in the Drosophila motor system induces aggregate deposition, endoplasmic reticulum disorganization, and chaperone up-regulation both in neurons and in muscles. Our integrated analysis of the pathogenic effect of the T46I mutation and the previously identified P56S mutation indicate extensive commonalities in the disease mechanism for these two mutations. In summary, we show that this newly identified mutation in human FALS has a pathogenic effect, supporting and reinforcing the role of VAPB as a causative gene of ALS.

Original languageEnglish
Pages (from-to)40266-40281
Number of pages16
JournalJournal of Biological Chemistry
Issue number51
Publication statusPublished - 17 Dec 2010

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