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Regional genomic instability predisposes to complex dystrophin gene rearrangements

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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.

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Acknowledgments

We thank Dr. Svetlana A. Yatsenko for helpful discussions and Ms. Weihong Jin and Ms. Hoang Pham for their technical assistance.

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  1. Junko Oshima

    Present address: Department of Pathology, University of Washington, Seattle, WA, 98195, USA

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX, 77030, USA

    Junko Oshima, Jennifer A. Lee, Amy M. Breman, Eric S. Schmitt, Lisa D. White, Christine M. Eng & Daniela del Gaudio

  2. Huffington Center on Aging, Baylor College of Medicine, Houston, TX, 77030, USA

    Daniel B. Magner

  3. Metro Health Medical Center, Cleveland, OH, 44109, USA

    Carol A. Crowe & Michelle Merrill

  4. Division of Genetics and Metabolism, Miami Children’s Hospital, Miami, FL, 33155, USA

    Parul Jayakar & Aparna Rajadhyaksha

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  1. Junko Oshima
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Correspondence to Christine M. Eng.

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Oshima, J., Magner, D.B., Lee, J.A. et al. Regional genomic instability predisposes to complex dystrophin gene rearrangements. Hum Genet 126, 411–423 (2009). https://doi.org/10.1007/s00439-009-0679-9

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