title: Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis.
abstract: BACKGROUND
  Hereditary spastic paraparesis is a genetically heterogeneous condition. Recently, mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21-22.
  
  
  OBJECTIVE
  To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene (SPG4) on chromosome 2p21-22.
  
  
  METHODS
  DNA from 32 patients (12 from families known to be linked to SPG4) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing. All patients were also examined clinically.
  
  
  RESULTS
  Thirteen SPG4 mutations were identified, 11 of which are novel. These mutations include missense, nonsense, frameshift, and splice site mutations, the majority of which affect the AAA cassette. We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation.
  
  
  CONCLUSIONS
  Recurrent mutations in the spastin gene are uncommon. This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis. Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients.
authors.affiliation: Human Molecular Genetics Unit, School of Biochemistry and Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4AA, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Lindsey
authors.forename: M E
authors.initials: ME
authors.lastname: Lusher
authors.forename: C J
authors.initials: CJ
authors.lastname: McDermott
authors.forename: K D
authors.initials: KD
authors.lastname: White
authors.forename: E
authors.initials: E
authors.lastname: Reid
authors.forename: D C
authors.initials: DC
authors.lastname: Rubinsztein
authors.forename: R
authors.initials: R
authors.lastname: Bashir
authors.forename: J
authors.initials: J
authors.lastname: Hazan
authors.forename: P J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: K M
authors.initials: KM
authors.lastname: Bushby
mesh_terms: D000251:Adenosine Triphosphatases; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020336:Paraparesis, Spastic / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D000074181:Spastin; D006113:United Kingdom
chemical_list: D002135:Calcium-Binding Proteins; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human