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Published online before print March 5, 2008, doi:10.1212/01.wnl.0000289760.85237.4e)
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NEUROLOGY 2008;70:1179-1185
© 2008 American Academy of Neurology

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.

Address correspondence and reprint requests to Dr. J. Landers, MGH East, Room 3216, Bldg. 149, 13th Street, Charlestown, MA 02129 jelanders{at}partners.org

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.

Abbreviations: ALS = amyotrophic lateral sclerosis; ER = endoplasmic reticulum; FALS = familial ALS; SALS = sporadic ALS; VAPB = vesicle-associated membrane protein B.

Supplemental data at www.neurology.org

Editorial, page 1161

e-Pub ahead of print on March 5, 2008, at www.neurology.org.

The Day Neuromuscular Research Laboratory (R.H.B.) receives support from the National Institute of Neurological Disease and Stroke, the National Institute for Aging, the Angel Fund, the ALS Association, Project ALS, the Pierre L. de Bourgknect ALS Research Foundation, and the Al-Athel ALS Foundation. R.H.B. and J.E.L. received support for this project from the ALS Therapy Alliance. J.D.G. receives support from the Packard Center for ALS Research. A.A.-C. is supported by the Medical Research Council, Motor Neurone Disease Association, ALS Association, and Project ALS. M.M.M. is supported by a Ruth L. Kirschstein National Research Service Award (NIH/National Institute of Neurological Disorders and Stroke, F32NS048809). P.S. is supported through the auspices of Dr. H.R. Horvtiz, an Investigator of the Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology.

Disclosure: The authors report no conflicts of interest.

Received May 17, 2007. Accepted in final form August 30, 2007.






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