title: A polymorphic Alu insertion that mediates distinct disease-associated deletions.
abstract: Large deletions that are associated with insertions of Alu-derived sequence represent a rare, but potentially unique class of alterations. Whether they form by a one-step mechanism or by a primary insertion step followed by an independent secondary deletion step is not clear. We resolved two disease-associated SPAST deletions, which involve distinct exons by long range PCR. Alu-derived sequence was observed between the breakpoints in both cases. The intronic regions that represent the targets of potentially involved Alu retrotransposition events overlapped. Microsatellite- and SNP-based haplotyping indicated that both deletions originated on one and the same founder allele. Our data suggest that the deletions are best explained by two-step insertion-deletion scenarios for which a single Alu retrotransposition event represents the shared primary step. This Alu then mediated one of the deletions by non-homologous end joining and the other by non-allelic homologous recombination. Our findings thus strongly argue for temporal separation of insertion and deletion in Alu insertion-associated deletions. They also suggest that certain Alu integrations confer a general increase in local genomic instability, and that this explains why they are usually not detected during the probably short time that precedes the rearrangements they mediate.
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
authors.forename: Amir
authors.initials: A
authors.lastname: Jahic
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Erichsen
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
authors.forename: Thomas
authors.identifier: 0000-0003-4839-3117
authors.initials: T
authors.lastname: Deufel
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.|Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Chantal M
authors.initials: CM
authors.lastname: Tallaksen
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000483:Alleles; D020087:Alu Elements / Q000235:genetics*; D056905:Chromosome Breakpoints; D005091:Exons; D017353:Gene Deletion; D059765:Homologous Recombination; D006801:Humans; D016254:Mutagenesis, Insertional; D010264:Paraplegia / Q000175:diagnosis / Q000235:genetics*; D011110:Polymorphism, Genetic; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis / Q000235:genetics*; D000074181:Spastin
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human