title: Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using genetic linkage and whole exome sequencing.
  
  
  METHODS
  Genetic linkage analysis was performed in this family using Illumina single nucleotide polymorphism chips. Whole exome sequencing was then undertaken on DNA samples from 2 affected family members using an Illumina 2000 HiSeq platform in pursuit of potentially pathogenic genetic variants that comigrate with the disease in this pedigree. Variants meeting these criteria were then screened in all affected individuals.
  
  
  RESULTS
  A novel mutation (p.R191G) in the valosin-containing protein (VCP) gene was identified in the index family. Direct sequencing of the VCP gene in a panel of DNA from 274 unrelated individuals with familial amyotrophic lateral sclerosis (FALS) revealed 5 additional mutations. Among them, 2 were previously identified in pedigrees with a constellation of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) and in FALS, and 2 other mutations (p.R159C and p.R155C) in IBMPFD alone. We did not detect VCP gene mutations in DNA from 178 cases of sporadic amyotrophic lateral sclerosis.
  
  
  CONCLUSIONS
  We report a novel VCP mutation identified in an amyotrophic lateral sclerosis family (p.R191G) with atypical clinical features. In our experience, VCP mutations arise in approximately 1.5% of FALS cases. Our study supports the view that motor neuron disease is part of the clinical spectrum of VCP-associated disease.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Paloma
authors.initials: P
authors.lastname: González-Pérez
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Cirulli
authors.forename: Vivian E
authors.initials: VE
authors.lastname: Drory
authors.forename: Ron
authors.initials: R
authors.lastname: Dabby
authors.forename: Puiu
authors.initials: P
authors.lastname: Nisipeanu
authors.forename: Ralph L
authors.initials: RL
authors.lastname: Carasso
authors.forename: Menachem
authors.initials: M
authors.lastname: Sadeh
authors.forename: Andrew
authors.initials: A
authors.lastname: Fox
authors.forename: Barry W
authors.initials: BW
authors.lastname: Festoff
authors.forename: Peter C
authors.initials: PC
authors.lastname: Sapp
authors.forename: Diane
authors.initials: D
authors.lastname: McKenna-Yasek
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Sergiu C
authors.initials: SC
authors.lastname: Blumen
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein