title: Regional genomic instability predisposes to complex dystrophin gene rearrangements.
abstract: Mutations in the dystrophin gene (DMD) cause Duchenne and Becker muscular dystrophies and the majority of cases are due to DMD gene rearrangements. Despite the high incidence of these aberrations, little is known about their causative molecular mechanism(s). We examined 792 DMD/BMD clinical samples by oligonucleotide array-CGH and report on the junction sequence analysis of 15 unique deletion cases and three complex intragenic rearrangements to elucidate potential underlying mechanism(s). Furthermore, we present three cases with intergenic rearrangements involving DMD and neighboring loci. The cases with intragenic rearrangements include an inversion with flanking deleted sequences; a duplicated segment inserted in direct orientation into a deleted region; and a splicing mutation adjacent to a deletion. Bioinformatic analysis demonstrated that 7 of 12 breakpoints combined among 3 complex cases aligned with repetitive sequences, as compared to 4 of 30 breakpoints for the 15 deletion cases. Moreover, the inversion/deletion case may involve a stem-loop structure that has contributed to the initiation of this rearrangement. For the duplication/deletion and splicing mutation/deletion cases, the presence of the first mutation, either a duplication or point mutation, may have elicited the deletion events in an attempt to correct preexisting mutations. While NHEJ is one potential mechanism for these complex rearrangements, the highly complex junction sequence of the inversion/deletion case suggests the involvement of a replication-based mechanism. Our results support the notion that regional genomic instability, aided by the presence of repetitive elements, a stem-loop structure, and possibly preexisting mutations, may elicit complex rearrangements of the DMD gene.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Oshima
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Magner
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lee
authors.forename: Amy M
authors.initials: AM
authors.lastname: Breman
authors.forename: Eric S
authors.initials: ES
authors.lastname: Schmitt
authors.forename: Lisa D
authors.initials: LD
authors.lastname: White
authors.forename: Carol A
authors.initials: CA
authors.lastname: Crowe
authors.forename: Michelle
authors.initials: M
authors.lastname: Merrill
authors.forename: Parul
authors.initials: P
authors.lastname: Jayakar
authors.forename: Aparna
authors.initials: A
authors.lastname: Rajadhyaksha
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.forename: Daniela
authors.initials: D
authors.lastname: del Gaudio
mesh_terms: D017398:Alternative Splicing; D055028:Comparative Genomic Hybridization; D019295:Computational Biology / Q000379:methods; D016189:Dystrophin / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016189:Dystrophin