title: Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia.
abstract: BACKGROUND
  Hereditary spastic paraplegia (HSP) is a neurodegenerative disease characterized by progressive spasticity and weakness of the lower limbs. The most common form of HSP is caused by mutations in the SPG4 gene, which codes for spastin, an adenosine triphosphatase with various cellular activities (AAA) protein family member.
  
  
  OBJECTIVE
  To investigate a large collection of predominantly North American patients with HSP for mutations in the spastin encoding gene, SPG4.
  
  
  METHODS
  DNA from 76 unrelated affected individuals was studied for mutations by single-stranded conformational polymorphism analysis and direct sequencing. Each new variant identified was then analyzed in 80 control subjects to determine whether the variant is a common polymorphism or a rare mutation. All DNA samples were amplified by polymerase chain reaction, followed by electrophoresis and autoradiography.
  
  
  RESULTS
  We identified 8 novel mutations and 5 previously reported mutations in 15 affected individuals. The novel mutations are 4 missense, 1 nonsense, 1 frameshift, and 2 splice mutations. Two polymorphisms (one in an affected individual) were also identified.
  
  
  CONCLUSIONS
  Our collection of families with HSP is different on a genetic level from those previously described. The percentage of our families with a SPG4 mutation is 10% lower than the 40% estimate of families with autosomal dominant HSP noted to be linked to this locus, and splice mutations are not predominant in our collection. Interestingly, we also identified 2 recurring mutations in specific populations (R562Q and G559D), which may facilitate the development of future spastin diagnostic testing in these populations.
authors.affiliation: Centre for Research in Neuroscience, The Montreal General Hospital Research Institute, 1650 Cedar Ave, Room L7-224, Montreal, Quebec, Canada H3G 1A4.
authors.forename: Inge A
authors.initials: IA
authors.lastname: Meijer
authors.forename: Collette K
authors.initials: CK
authors.lastname: Hand
authors.forename: P
authors.initials: P
authors.lastname: Cossette
authors.forename: Denise A
authors.initials: DA
authors.lastname: Figlewicz
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D000074181:Spastin
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human