title: High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia.
abstract: BACKGROUND
  Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease. The most frequent cause of autosomal dominant HSP is mutation of SPAST (SPG4 locus), but additional pedigrees remain mutation negative by conventional screening despite linkage to SPG4.
  
  
  OBJECTIVE
  To determine the frequency of genomic copy number aberrations of SPAST in autosomal dominant HSP.
  
  
  METHODS
  We developed and validated a multiplex ligation-dependent probe amplification assay targeting SPAST and SPG3A, another gene frequently involved in autosomal dominant HSP. In a multicenter study we subsequently investigated 65 index patients with autosomal dominant HSP, all of whom had previously been screened negative for SPAST mutations. Independent secondary samples, additional family members, and cDNA were analyzed to confirm positive findings.
  
  
  RESULTS
  Aberrant MLPA profiles were identified in 12 cases (18%). They exclusively affect SPAST, represent deletions, segregate with the disease, and are largely pedigree specific. Internal SPAST deletions entail expression of correspondingly shortened transcripts, which vary in stability. Age at onset in SPAST deletion carriers does not differ from that associated with other SPAST mutations.
  
  
  CONCLUSIONS
  Partial SPAST deletions, but not SPAST amplifications and SPG3A copy number aberrations, represent an underestimated cause of autosomal dominant hereditary spastic paraplegia. Partial SPAST deletions are likely to act via haploinsufficiency.
authors.affiliation: Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum Jena, D-07740 Jena, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Beetz
authors.forename: A O H
authors.initials: AO
authors.lastname: Nygren
authors.forename: J
authors.initials: J
authors.lastname: Schickel
authors.forename: M
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: K
authors.initials: K
authors.lastname: Bürk
authors.forename: G
authors.initials: G
authors.lastname: Heide
authors.forename: J
authors.initials: J
authors.lastname: Kassubek
authors.forename: S
authors.initials: S
authors.lastname: Klimpe
authors.forename: T
authors.initials: T
authors.lastname: Klopstock
authors.forename: F
authors.initials: F
authors.lastname: Kreuz
authors.forename: S
authors.initials: S
authors.lastname: Otto
authors.forename: R
authors.initials: R
authors.lastname: Schüle
authors.forename: L
authors.initials: L
authors.lastname: Schöls
authors.forename: A-D
authors.initials: AD
authors.lastname: Sperfeld
authors.forename: O W
authors.initials: OW
authors.lastname: Witte
authors.forename: T
authors.initials: T
authors.lastname: Deufel
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics*; D006238:Haploidy; D006801:Humans; D008875:Middle Aged; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D000074181:Spastin
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human