title: Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia.
abstract: OBJECTIVE
  Autosomal dominant spastic paraplegia, type 4 (SPG4), a debilitating disorder of progressive spasticity and weakness of the lower limbs, results from heterozygous mutations in the SPAST gene. The full spectrum of SPAST mutations causing SPG4 and their mechanisms of formation remain to be determined.
  
  
  METHODS
  We used multiplex ligation-dependent probe amplification, locus-specific array comparative genomic hybridization, and breakpoint DNA sequencing to identify and describe genomic rearrangements in three patients with a clinical presentation of hereditary spastic paraplegia.
  
  
  RESULTS
  We describe three SPG4 patients with intragenic rearrangements in SPAST; all specifically delete the final exon, exon 17. Breakpoint sequence analyses provide evidence for Alu-specific microhomology-mediated deletion as the mechanism of exon loss; one complex rearrangement apparently occurred by multiple Alu-facilitated template switches.
  
  
  CONCLUSIONS
  We hypothesize that the high concentration of Alu family members in the introns and flanking sequence of SPAST may predispose to intragenic rearrangements. Thus, Alu-specific microhomology-mediated intragenic rearrangements in SPAST may be a common cause of SPG4. Furthermore, we propose that genomic deletions encompassing the final exon of SPAST may affect expression of SLC30A6, the most proximal downstream locus and a gene that has been implicated in the pathogenesis of Alzheimer disease, potentially explaining recent reports of dementia in selected SPG4 patients.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Boone
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.forename: Charles F
authors.initials: CF
authors.lastname: Towne
authors.forename: Sat Dev
authors.initials: SD
authors.lastname: Batish
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D020087:Alu Elements / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000235:genetics; D005091:Exons; D015870:Gene Expression; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D000074181:Spastin
chemical_list: D027682:Cation Transport Proteins; C504822:SLC30A6 protein, human; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human