Complex genomic rearrangements in the dystrophin gene due to replication-based mechanisms.
Complex genomic rearrangements in the dystrophin gene due to replication-based mechanisms.
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DOI：
10.1002/mgg3.108
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发表时间：
2014-11
影响因子：
2
通讯作者：
Ray, Peter N
中科院分区：
文献类型：
--
作者：
Baskin, Berivan;Stavropoulos, Dimitri J;Rebeiro, Paige A;Orr, Jennifer;Li, Martin;Steele, Leslie;Marshall, Christian R;Lemire, Edmond G;Boycott, Kym M;Gibson, William;Ray, Peter N
基因组重排，如基因内缺失和重复，是导致Duchenne和Becker肌营养不良症(D/BMD)的最常见的dystrophin基因突变类型。这些拷贝数变异(CNV)是非复发性的，可由非同源末端连接(NHEJ)或微同源介导的复制依赖重组(MMRDR)引起。我们利用MLPA/mRNA转录本分析/定制阵列比较杂交阵列(CGH)和断点序列分析相结合的方法对5例DMD患者进行了复杂的基因组重排，以探讨这些重排的机制。两名患者有复杂的重排，涉及断裂点的微同源。1例患者4号染色体89.7kb非连续插入DMD内含子43，涉及3个断裂点，在连接处有2-5kb的微同源性。第二例患者外显子44倒置，两侧有内含子缺失，每个内含子缺失两个断点连接，每个内含子显示2个碱基对的微同源性。第三例为女性，母亲等位基因DMD外显子47缺失，父亲等位基因MID1和DMD外显子45-49重复。另外两名患者在dystrophin基因内存在复杂的非连续复制。我们提出了一种基于复制的机制来处理所有五种复杂的DMD重排。这项研究确定了DMD的其他潜在机制，并提供了对这些基因组重排的分子基础的洞察。
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.