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Published online before print March 5, 2008, doi:10.1212/01.wnl.0000289760.85237.4e)
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Received May 17, 2007
Accepted August 30, 2007

New VAPB deletion variant and exclusion of VAPB mutations in familial ALS

J. E. Landers PhD*, A. L. Leclerc BA, L. Shi MD, A. Virkud , T. Cho BS, M. M. Maxwell PhD, A. F. Henry BS, M. Polak RN, J. D. Glass MD, T. J. Kwiatkowski MD, A. Al-Chalabi PhD, FRCP, C. E. Shaw MD, FRACP, P. N. Leigh FRCP, PhD, I. Rodriguez-Leyza MD, D. McKenna-Yasek RN, BSN, P. C. Sapp BS, and R. H. Brown Jr. MD, DPhil

From Cecil B. Day Laboratory for Neuromuscular Research (J.E.L., A.L.L., L.S., A.V., T.C., M.M.M., A.F.H., T.J.K., I.R.-L., D.M.-Y., P.C.S., R.H.B.), Massachusetts General Hospital East, Charlestown; Center for Neurodegenerative Disease (M.P., J.D.G.), School of Medicine, Emory University, Atlanta, GA; MRC Centre for Neurodegeneration Research (A.A.-C., C.E.S., P.N.L.), King's College London, Institute of Psychiatry, Department of Neurology, London, UK; Department of Neurology (I.R.-L.), Hospital Central, Colonia Universitaria, San Luis Potosi, Mexico; and Howard Hughes Medical Institute (P.C.S.), Department of Biology, Massachusetts Institute of Technology.


* To whom correspondence should be addressed. E-mail: jelanders{at}partners.org.

ABSTRACT

Objective:Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disorder involving upper and lower motor neurons. The vesicle-associated membrane protein B (VAPB ) gene has been genetically linked to ALS in several large Brazilian families in which the disorder is caused by a proline to serine mutation at codon 56 (P56S). No additional mutations have been identified.

Methods:To establish the prevalence of VAPB mutations, we screened 80 familial ALS samples by DNA sequencing.

Results:Our study failed to identify any novel VAPB gene mutations but identified a single Brazilian family harboring the P56S mutation. In a second familial ALS case, we identified a three–base pair deletion within exon 5 of the VAPB gene that deleted the serine residue at position 160 ({Delta}S160). This variant is detected in a normal population at low frequency (0.45%). Analyses of homology alignment and secondary structure predict that this deletion significantly alters the structure of VAPB, although a GFP-{Delta}S160 VAPB fusion protein demonstrates a wild-type subcellular localization. This contrasts the aberrant localization observed in a GFP-P56S VAPB fusion protein. The allele frequency of {Delta}S160 in patients with sporadic ALS does not differ significantly from that in the normal population.

Conclusions:Mutations in the VAPB gene are rare and the {Delta}S160 variant does not contribute to the development of amyotrophic lateral sclerosis.






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