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

J. E LANDERS; A. L LECLERC; A AL-CHALABI; C. E SHAW; P. N LEIGH; I RODRIGUEZ-LEYZA; D MCKENNA-YASEK; P. C SAPP; R. H BROWN; L SHI; A VIRKUD; T CHO; M. M MAXWELL; A. F HENRY; M POLAK; J. D GLASS; T. J KWIATKOWSKI

doi:10.1212/01.wnl.0000289760.85237.4e

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

Journal article

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

J. E LANDERS, A. L LECLERC, A AL-CHALABI, C. E SHAW, P. N LEIGH, I RODRIGUEZ-LEYZA, D MCKENNA-YASEK, P. C SAPP, R. H BROWN, L SHI, …

Neurology, Vol.70(14), pp.1179-1185

2008

DOI: 10.1212/01.wnl.0000289760.85237.4e

PMID: 18322265

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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.

Neurology

Biological and medical sciences

Medical sciences

Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases

Details

Title: Subtitle: New VAPB deletion variant and exclusion of VAPB mutations in familial ALS
Creators: J. E LANDERS - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
A. L LECLERC - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
A AL-CHALABI - MRC Centre for Neurodegeneration Research King's College London, Institute of Psychiatry, Department of Neurology, London, United Kingdom
C. E SHAW - MRC Centre for Neurodegeneration Research King's College London, Institute of Psychiatry, Department of Neurology, London, United Kingdom
P. N LEIGH - MRC Centre for Neurodegeneration Research King's College London, Institute of Psychiatry, Department of Neurology, London, United Kingdom
I RODRIGUEZ-LEYZA - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
D MCKENNA-YASEK - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
P. C SAPP - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
R. H BROWN - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
L SHI - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
A VIRKUD - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
T CHO - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
M. M MAXWELL - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
A. F HENRY - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
M POLAK - Center for Neurodegenerative Disease School of Medicine, Emory University, Atlanta, GA, United States
J. D GLASS - Center for Neurodegenerative Disease School of Medicine, Emory University, Atlanta, GA, United States
T. J KWIATKOWSKI - Cecil B. Day Laboratory for Neuromuscular Research Massachusetts General Hospital East, Charlestown, United States
Resource Type: Journal article
Publication Details: Neurology, Vol.70(14), pp.1179-1185
Publisher: Lippincott Williams & Wilkins; Hagerstown, MD
DOI: 10.1212/01.wnl.0000289760.85237.4e
PMID: 18322265
ISSN: 0028-3878
eISSN: 1526-632X
Language: English
Date published: 2008
Academic Unit: Neurology; Iowa Neuroscience Institute
Record Identifier: 9984071650402771

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