title: 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 (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.
authors.affiliation: Cecil B. Day Laboratory for Neuromuscular Research, Massachusetts General Hospital East, Charlestown, MA, USA. jelanders@partners.org
authors.forename: J E
authors.initials: JE
authors.lastname: Landers
authors.forename: A L
authors.initials: AL
authors.lastname: Leclerc
authors.forename: L
authors.initials: L
authors.lastname: Shi
authors.forename: A
authors.initials: A
authors.lastname: Virkud
authors.forename: T
authors.initials: T
authors.lastname: Cho
authors.forename: M M
authors.initials: MM
authors.lastname: Maxwell
authors.forename: A F
authors.initials: AF
authors.lastname: Henry
authors.forename: M
authors.initials: M
authors.lastname: Polak
authors.forename: J D
authors.initials: JD
authors.lastname: Glass
authors.forename: T J
authors.initials: TJ
authors.lastname: Kwiatkowski
authors.forename: A
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: C E
authors.initials: CE
authors.lastname: Shaw
authors.forename: P N
authors.initials: PN
authors.lastname: Leigh
authors.forename: I
authors.initials: I
authors.lastname: Rodriguez-Leyza
authors.forename: D
authors.initials: D
authors.lastname: McKenna-Yasek
authors.forename: P C
authors.initials: PC
authors.lastname: Sapp
authors.forename: R H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D017510:Protein Folding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D011993:Recombinant Fusion Proteins; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins