A common molecular basis for rearrangement disorders on chromosome 22q11
A common molecular basis for rearrangement disorders on chromosome 22q11
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DOI：
10.1093/hmg/8.7.1157
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发表时间：
1999-07-01
影响因子：
3.5
通讯作者：
Morrow, BE
中科院分区：
文献类型：
--
作者：
Edelmann, L;Pandita, RK;Morrow, BE
染色体22 q11区域易发生与先天性异常疾病和恶性肿瘤相关的重排。猫眼综合征、der（22）综合征和腭心面综合征/DiGeorge综合征（VCFS/DGS）分别与染色体22 q11部分的四体性、三体性和单体性相关，其中VCFS/DGS是最常见的与22 q11重排相关的综合征。为了确定22 q11上是否存在易于重排的特定区域，通过单倍型分析确定了大量VCFS/DGS患者的缺失终点。大多数VCFS/DGS患者具有相似的3 Mb缺失，一些患者具有导致1.5 Mb缺失的嵌套远端缺失断点，少数罕见患者具有独特的缺失或易位。该疾病在人群中的高患病率和大多数病例偶发的事实表明，断裂点处或附近的序列赋予染色体重排的易感性。为了研究这一假设，我们从VCFS/DGS患者中开发了具有所有三类缺失的仓鼠-人体细胞杂交细胞系，我们现在表明断点发生在类似的低拷贝重复序列中，称为LCR 22。为了进一步支持这一想法，我们确定了一个家族，该家族携带在VCFS/DGS患者中缺失的相同3 Mb区域的间质重复。我们提出模型来解释LCR 22如何介导不同的同源重组事件，从而产生与先天性异常疾病相关的许多重排。我们在22 q11上发现了另外5个LCR 22拷贝，它们可能介导导致疾病的其他重排。
The chromosome 22q11 region is susceptible to rearrangements that are associated with congenital anomaly disorders and malignant tumors. Three congenital anomaly disorders, cat-eye syndrome, der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, respectively, for part of chromosome 22q11, VCFS/DGS is the most common syndrome associated with 22q11 rearrangements. In order to determine whether there are particular regions on 22q11 that are prone to rearrangements, the deletion end-points in a large number of VCFS/DGS patients were defined by haplotype analysis. Most VCFS/DGS patients have a similar 3 Mb deletion, some have a nested distal deletion breakpoint resulting in a 1.5 Mb deletion and a few rare patients have unique deletions or translocations. The high prevalence of the disorder in the population and the fact that most cases occur sporadically suggest that sequences at or near the breakpoints confer susceptibility to chromosome rearrangements. To investigate this hypothesis, we developed hamster-human somatic hybrid cell lines from VCFS/DGS patients with all three classes of deletions and we now show that the breakpoints occur within similar low copy repeats, termed LCR22s. To support this idea further, we identified a family that carries an interstitial duplication of the same 3 Mb region that is deleted in VCFS/DGS patients, We present models to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders. We identified five additional copies of the LCR22 on 22q11 that may mediate other rearrangements leading to disease.