title: Novel SPG3A and SPG4 mutations in dominant spastic paraplegia families.
abstract: OBJECTIVE
  The hereditary spastic paraplegias (HSP) are a genetically and clinically heterogeneous group of neurodegenerative disorders, mainly characterized by a progressive spasticity and weakness of the lower limbs. Mutations in the SPG4 and SPG3A genes are responsible for approximately 50% of autosomal dominant HSP. To genetically diagnose the Portuguese families with HSP, mutation analysis was performed for the SPG4 and SPG3A genes.
  
  
  METHODS
  Analysis was performed by polymerase chain reaction, followed by denaturing high performance liquid chromatography (DHPLC), in 61 autosomal dominant (AD)-HSP families and 19 unrelated patients without family history.
  
  
  RESULTS
  Ten novel mutations were identified: one in the SPG3A and nine in the SPG4 genes; three known mutations in the SPG4 were also found. Most of the novel mutations were frameshift or nonsense (80%), resulting in a dysfunctional protein.
  
  
  CONCLUSIONS
  The SPG4 and SPG3A analysis allowed the identification of 10 novel mutations and the genetic diagnosis of approximately a quarter of our AD-HSP families.
authors.affiliation: UnIGENe, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal.
authors.forename: J L
authors.initials: JL
authors.lastname: Loureiro
authors.forename: L
authors.initials: L
authors.lastname: Miller-Fleming
authors.forename: C
authors.initials: C
authors.lastname: Thieleke-Matos
authors.forename: P
authors.initials: P
authors.lastname: Magalhães
authors.forename: V T
authors.initials: VT
authors.lastname: Cruz
authors.forename: P
authors.initials: P
authors.lastname: Coutinho
authors.forename: J
authors.initials: J
authors.lastname: Sequeiros
authors.forename: I
authors.initials: I
authors.lastname: Silveira
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D017668:Age of Onset; D000595:Amino Acid Sequence; D002851:Chromatography, High Pressure Liquid; D005190:Family; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D019204:GTP-Binding Proteins; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010264:Paraplegia / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020539:Sequence Analysis, Protein; D000074181:Spastin
chemical_list: D008565:Membrane Proteins; C440006:ATL1 protein, human; D000251:Adenosine Triphosphatases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D000074181:Spastin; C400283:SPAST protein, human