Copy-Number Gains of HUWE1 Due to Replication- and Recombination-Based Rearrangements
Copy-Number Gains of HUWE1 Due to Replication- and Recombination-Based Rearrangements
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DOI：
10.1016/j.ajhg.2012.06.010
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发表时间：
2012-08-10
影响因子：
9.8
通讯作者：
Marynen, Peter
中科院分区：
文献类型：
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作者：
Froyen, Guy;Belet, Stefanie;Marynen, Peter
我们先前报道了在Xp11.22处的非复发性重叠重复，在最小重叠区域中，患有非综合征性智力残疾（ID）的个体中含有HSD 17 B10，HUWE 1和microRNA miR-98和let-7 f-2。在这里，我们描述了6个额外的个人与非综合征ID和重叠的微重复分离的家庭。高分辨率映射的12个拷贝数的增益减少了最小重复区域的HUWE 1基因座。因此，检测到HUWE 1的mRNA水平增加，但未检测到HSD 17 B10。标记和SNP分析，以及两个从头事件的鉴定，表明父系来源的染色体内重复事件。在4个独立的家族中，我们报告了一个多态性的70 kb重复拷贝数增加，其中包含HUWE 1的一部分（外显子28至3'非翻译区），包括miR-98和let-7 f-2。因此，我们的研究结果表明，HUWE 1是唯一剩下的剂量敏感基因与ID表型。交界处和计算机分析的断点区域表现出简单的微同源介导的重排提示基于复制的重复事件。有趣的是，在一个单一的家庭中，重复是通过非等位基因同源重组（NAHR）与HUWE 1侧翼不完美的低拷贝重复，这驱动了这种罕见的NAHR事件的使用。复发性部分HUWE 1拷贝数增加也是通过NAHR产生的，但在这里，使用的同源序列被鉴定为TcMAR-Tigger DNA元件，这是一种尚未报道的NAHR模板。总之，我们发现HUWE 1剂量增加会导致非综合征性ID，并证明Xp11.22区域易于发生基于重组和复制的重排。
We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, increased mRNA levels were detected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3' untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.