title: Hereditary spastic paraplegia: clinical genetic study of 15 families.
abstract: BACKGROUND
  Autosomal dominant hereditary spastic paraplegia (ADHSP) is mainly caused by mutations in the SPG4 gene, which encodes a new member of the AAA (adenosine triphosphatases associated with diverse cellular activities) protein family (spastin). Accumulation of genotype-phenotype correlation is important for better understanding of SPG4-linked hereditary spastic paraplegia.
  
  
  OBJECTIVE
  To perform a clinical and genetic study of families with ADHSP and to perform the functional analysis of the founder mutation discovered in the SPG4 gene.
  
  
  METHODS
  Genetic and clinical study. Patients Fifteen unrelated families with ADHSP originating from southern Scotland.
  
  
  METHODS
  Clinical assessment, linkage analysis, haplotype study, expression of mutant spastin protein in cultured cells.
  
  
  RESULTS
  Nine families with ADHSP were linked to the SPG4 locus at 2p21-p24. Sequence analysis of SPG4showed a novel N386S mutation in all 9 of these families. Expression of mutant spastin showed aberrant distribution in cultured cells. Haplotype analysis suggested the existence of a common founder. Clinical examination of the affected members carrying the mutation showed phenotypic variations including broad range of age at onset and disease duration and additional neurologic features such as mental retardation. Magnetic resonance imaging demonstrated unique features, including thin corpus callosum and atrophy of the cerebellum in 2 patients. Linkage and sequence analyses showed no evidence of linkage to the currently known ADHSP loci in the remaining 6 families.
  
  
  CONCLUSIONS
  A founder SPG4 mutation N386S was identified in the families with ADHSP originating from southern Scotland. Clinical investigation showed intrafamilial and interfamilial phenotypic variations. The genetic study demonstrated evidence of further genetic heterogeneity in ADHSP.
authors.affiliation: Laboratorio di Neurogenetica, Istituto di Ricovero e Cura a Carattere Scientifico, Santa Lucia, Rome, Italy. a.orlacchio@hsantalucia.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Orlacchio
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.forename: Antonio
authors.initials: A
authors.lastname: Totaro
authors.forename: Alessia
authors.initials: A
authors.lastname: Errico
authors.forename: Peter H
authors.initials: PH
authors.lastname: St George-Hyslop
authors.forename: Elena I
authors.initials: EI
authors.lastname: Rugarli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002648:Child; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D006801:Humans; D008297:Male; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074181:Spastin
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human