Journal
NEUROLOGY
Volume 70, Issue 14, Pages 1179-1185Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/01.wnl.0000289760.85237.4e
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Funding
- MRC [G0500289] Funding Source: UKRI
- Medical Research Council [G0500289, G0500289B] Funding Source: researchfish
- Howard Hughes Medical Institute Funding Source: Medline
- Medical Research Council [G0500289] Funding Source: Medline
- NINDS NIH HHS [F32NS048809] Funding Source: Medline
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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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