Edelmann L, Spiteri E, Koren K, Pulijaal V, Bialer M G, Shanske A, Goldberg R, Morrow B E
Department of Molecular Genetics, Albert Einstein College of Medicine, New York, NY, USA.
Am J Hum Genet. 2001 Jan;68(1):1-13. doi: 10.1086/316952. Epub 2000 Nov 28.
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&rcolon;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.
染色体组型t(11;22)易位是人类已知的唯一常见的非罗伯逊易位。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)易位断点定位到22q11上一个名为“LCR22”的低拷贝重复序列区域内，以及11q23上一个富含AT的重复序列内。LCR22s参与介导22q11上的不同重排，通过同源重组机制导致心脏颜面综合征/迪乔治综合征和猫眼综合征。LCR22s包含富含AT的重复序列，表明此类重复序列可能介导t(11;22)易位。为了确定易位的分子基础，我们克隆并测序了13名无关携带者的衍生11号和22号染色体中的t(11;22)断点，其中包括2例新发病例和der(22)综合征后代。我们发现，在所有检测的病例中，相互交换发生在11号染色体q23和22号染色体q11上相似的富含AT的重复序列之间。为了理解其机制，我们检查了衍生染色体中断点区间的序列，并将其与推导的正常染色体序列进行比较。通过链内碱基配对，在亲代染色体上可以形成一个具有近乎完美发夹结构的富含AT的回文序列。两个衍生染色体中断点连接的序列表明，交换事件发生在回文序列的对称中心，这导致不同携带者在该区域出现小的、重叠的交错缺失。基于之前在不同生物体中进行的研究，我们推测双链断裂可能发生在回文序列的中心，即假定发夹的末端，导致11号和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，从而导致回文序列的缺失和丢失，进而稳定DNA结构。
