RT Journal Article
SR Electronic
T1 New <em>VAPB</em> deletion variant and exclusion of <em>VAPB</em> mutations in familial ALS
JF Neurology
JO Neurology
FD Lippincott Williams &amp; Wilkins
SP 1179
OP 1185
DO 10.1212/01.wnl.0000289760.85237.4e
VO 70
IS 14
A1 Landers, J. E.
A1 Leclerc, A. L.
A1 Shi, L.
A1 Virkud, A.
A1 Cho, T.
A1 Maxwell, M. M.
A1 Henry, A. F.
A1 Polak, M.
A1 Glass, J. D.
A1 Kwiatkowski, T. J.
A1 Al-Chalabi, A.
A1 Shaw, C. E.
A1 Leigh, P. N.
A1 Rodriguez-Leyza, I.
A1 McKenna-Yasek, D.
A1 Sapp, P. C.
A1 Brown, R. H.
YR 2008
UL http://n.neurology.org/content/70/14/1179.abstract
AB 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 (ΔS160). 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-ΔS160 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 ΔS160 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 ΔS160 variant does not contribute to the development of amyotrophic lateral sclerosis. ALS=amyotrophic lateral sclerosis; ER=endoplasmic reticulum; FALS=familial ALS; SALS=sporadic ALS; VAPB=vesicle-associated membrane protein B.