AT-Rich Palindromes Mediate the Constitutional t(11;22) Translocation

Abstract

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.

Palindromic AT-rich repeat in theNF1gene is hypervariable in humans and evolutionarily conserved in primates

“…Recently, considerable data concerning PATRR-mediated translocations have been accumulated [Kehrer-Sawatzki et al, 1997;Kurahashi et al, 2000aKurahashi et al, , 2003Edelmann et al, 2001;Emanuel, 2001a, 2001b;Nimmakayalu et al, 2003;Gotter et al, 2004]. We previously proposed that PATRRs adopt a cruciform structure that mediates certain translocations, and that symmetry of the palindrome is likely to influence the susceptibility to translocation [Kurahashi and Emanuel, 2001a].…”

“…The first PATRR was identified at the breakpoint of the constitutional t(11;22) (q23;q11) [Kurahashi et al, 2000a]. During reconstruction of the original breakpoint sequences of chromosomes 11 and 22 from the der(11) and der(22) sequences of several t(11;22) carriers, we realized that the AT-rich sequences at the breakpoint were palindromic [Kurahashi et al, 2000a,b;Edelmann et al, 2001]. Since the PATRR in chromosome 11 (11PATRR) was deleted from the BAC encompassing the breakpoint, we analyzed the authentic 11PATRR with significant difficulty by using nested PCR followed by generation of a series of deletion mutants of the PCR products.…”

Non-B DNA Conformations, Genomic Rearrangements, and Human Disease

“…Sequence analyses of constitutional translocation breakpoints between chromosome 22 and chromosomes 1, 4, 11, or 17 show the hallmarks of cruciform DNA. For example, the breakpoints on LCR-B clustered in a narrow IR ATrich region that, in conjunction with flanking NF-1-like sequences (17,22), is predicted to form a ϳ600-bp-long cruciform. Furthermore, the clustering occurred within 15 bp from the IR center and involved the symmetric deletion of a few base pairs on either side of the IR apex (23), consistent with the prediction that cruciform loops are susceptible to cleavage and hence to repair (24).…”

Recent advance in our understanding of the molecular nature of chromosomal abnormalities

“…A more detailed characterization of the junction involved further revealed remnants of DSBs at the center of the two PATRRs, followed by repair through the non-homologous end joining pathway. [29][30][31][32] Two unrelated constitutional t(17;22)(q11;q11) translocations associated with NF1 disease have been reported. 33,34 These two translocations disrupt the NF1 gene on 17q11, which produces the NF1 phenotype in the affected patients.…”