AT-rich palindromes mediate the constitutional t(11;22) translocation
AT-rich palindromes mediate the constitutional t(11;22) translocation
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DOI：
10.1086/316952
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发表时间：
2001-01-01
影响因子：
9.8
通讯作者：
Morrow, BE
中科院分区：
文献类型：
--
作者：
Edelmann, L;Spiteri, E;Morrow, BE
构造型t（11;22）易位是人类唯一已知的复发性非罗伯逊易位。后代易患der（22）综合征，这是一种由3:1减数分裂不分离事件引起的严重先天性异常疾病。我们之前将t（11;22）易位断点定位在22q11上被称为“LCR22”的低拷贝重复和11q23上富含at的重复中的一个区域。lcr22参与介导22q11的不同重排，通过同源重组机制导致心面综合征/DiGeorge综合征和猫眼综合征。lcr22含有富含at的重复序列，表明这些重复序列可能介导t（11;22）易位。为了确定易位的分子基础，我们克隆了13个不相关携带者的衍生11和22染色体的t（11;22）断点，并对其进行了测序，其中包括两个新生病例和der（22）综合征后代。我们发现，在所检查的所有病例中，在11q23和22q11两条染色体上相似的富含at的重复序列之间发生了互惠交换。为了了解这一机制，我们检查了衍生染色体的断点间隔序列，并将其与推断的正常染色体序列进行了比较。通过链内碱基配对，可以在亲本染色体上形成一个具有近乎完美的发夹的富含at的回文序列。两个衍生物的断点连接序列表明，交换事件发生在回文的对称中心，这导致了不同载体在该区域的小而重叠的交错缺失。基于之前在不同生物中进行的研究，我们假设双链断裂可能发生在回文的中心，即假定的发夹的尖端，导致11号染色体和22号染色体上相似的富含at的序列之间发生非法重组事件，导致回文的缺失和丢失，从而稳定DNA结构。
The constitutional t(11;22) translocation is the only known recurrent non-Robertsonian translocation in humans. Offspring are susceptible to der(22) syndrome, a severe congenital anomaly disorder caused by 3:1 meiotic nondisjunction events. We previously localized the t(11;22) translocation breakpoint to a region on 22q11 within a low-copy repeat termed "LCR22" and within an AT-rich repeat on 11q23. The LCR22s are implicated in mediating different rearrangements on 22q11, leading to velocardiofacial syndrome/DiGeorge syndrome and cat-eye syndrome by homologous recombination mechanisms. The LCR22s contain AT-rich repetitive sequences, suggesting that such repeats may mediate the t(11;22) translocation. To determine the molecular basis of the translocation, we cloned and sequenced the t(11;22) breakpoint in the derivative 11 and 22 chromosomes in 13 unrelated carriers, including two de novo cases and der(22) syndrome offspring. We found that, in all cases examined, the reciprocal exchange occurred between similar AT-rich repeats on both chromosomes 11q23 and 22q11. To understand the mechanism, we examined the sequence of the breakpoint intervals in the derivative chromosomes and compared this with the deduced normal chromosomal sequence. A palindromic AT-rich sequence with a near-perfect hairpin could form, by intrastrand base-pairing, on the parental chromosomes. The sequence of the breakpoint junction in both derivatives indicates that the exchange events occurred at the center of symmetry of the palindromes, and this resulted in small, overlapping staggered deletions in this region among the different carriers. On the basis of previous studies performed in diverse organisms, we hypothesize that double-strand breaks may occur in the center of the palindrome, the tip of the putative hairpin, leading to illegitimate recombination events between similar AT-rich sequences on chromosomes 11 and 22, resulting in deletions and loss of the palindrome, which then could stabilize the DNA structure.