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

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 (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.