Complex genomic rearrangements in the dystrophin gene due to replication-based mechanisms.

Autor: Baskin B; Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University Uppsala, Sweden ; The Centre for Applied Genomics, The Hospital for Sick Children Toronto, Ontario, Canada., Stavropoulos DJ; The Centre for Applied Genomics, The Hospital for Sick Children Toronto, Ontario, Canada ; Department of Laboratory Medicine and Pathology, University of Toronto Toronto, Ontario, Canada ; Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada., Rebeiro PA; The Centre for Applied Genomics, The Hospital for Sick Children Toronto, Ontario, Canada., Orr J; Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada., Li M; Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada., Steele L; Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada., Marshall CR; The Centre for Applied Genomics, The Hospital for Sick Children Toronto, Ontario, Canada ; Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada., Lemire EG; Division of Medical Genetics, Royal University Hospital & University of Saskatchewan Saskatoon, Saskatchewan, Canada., Boycott KM; Department of Genetics, Children's Hospital of Eastern Ontario Ottawa, Ontario, Canada., Gibson W; Department of Medical Genetics, Child and Family Research Institute, The University of British Columbia Vancouver, British Columbia, Canada., Ray PN; The Centre for Applied Genomics, The Hospital for Sick Children Toronto, Ontario, Canada ; Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada ; Department of Molecular Genetics, The University of Toronto Toronto, Ontario, Canada.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2014 Nov; Vol. 2 (6), pp. 539-47. Date of Electronic Publication: 2014 Sep 15.
DOI: 10.1002/mgg3.108
Abstrakt: Genomic rearrangements such as intragenic deletions and duplications are the most prevalent type of mutations in the dystrophin gene resulting in Duchenne and Becker muscular dystrophy (D/BMD). These copy number variations (CNVs) are nonrecurrent and can result from either nonhomologous end joining (NHEJ) or microhomology-mediated replication-dependent recombination (MMRDR). We characterized five DMD patients with complex genomic rearrangements using a combination of MLPA/mRNA transcript analysis/custom array comparative hybridization arrays (CGH) and breakpoint sequence analysis to investigate the mechanisms for these rearrangements. Two patients had complex rearrangements that involved microhomologies at breakpoints. One patient had a noncontiguous insertion of 89.7 kb chromosome 4 into intron 43 of DMD involving three breakpoints with 2-5 bp microhomology at the junctions. A second patient had an inversion of exon 44 flanked by intronic deletions with two breakpoint junctions each showing 2 bp microhomology. The third patient was a female with an inherited deletion of exon 47 in DMD on the maternal allele and a de novo noncontiguous duplication of exons 45-49 in DMD and MID1 on the paternal allele. The other two patients harbored complex noncontiguous duplications within the dystrophin gene. We propose a replication-based mechanisms for all five complex DMD rearrangements. This study identifies additional underlying mechanisms in DMD, and provides insight into the molecular bases of these genomic rearrangements.
Databáze: MEDLINE
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