A Palindrome-Mediated Recurrent Translocation with 3:1 Meiotic Nondisjunction: The t(8;22)(q24.13;q11.21)

Sheridan, Molly B.; Kato, Takema; Haldeman-Englert, Chad R.; Jalali, G. Reza; Milunsky, Jeff M.; Zou, Ying; Klaes, Ruediger; Gimelli, G.; Gimelli, Stefania; Gemmill, Robert M.; Drabkin, Harry A.; Hacker, April M.; Brown, Julia; Tomkins, David F; Shaikh, Tamim H.; Kurahashi, Hiroki; Zackai, Elaine H.; Emanuel, Beverly S.

doi:10.1016/j.ajhg.2010.07.002

Cited by 45 publications

(50 citation statements)

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“…Thus, we proposed that the palindromic sequences form a cruciform conformation in vivo, and this conformation could induce DNA breakage that results in illegitimate joining, leading to a reciprocal translocation. To date, more than five other translocation-associated PATRRs have been identified, suggesting that palindrome-mediated chromosomal translocations are one of the important pathways generating GCRs in humans [14][15][16][17][18] .…”

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Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations

et al. 2013

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Gross chromosomal rearrangements (GCRs), such as translocations, deletions or inversions, are often generated by illegitimate repair between two DNA breakages at regions with nucleotide sequences that might potentially adopt a non-B DNA conformation. We previously established a plasmid-based model system that recapitulates palindrome-mediated recurrent chromosomal translocations in humans, and demonstrated that cruciform DNA conformation is required for the translocation-like rearrangements. Here we show that two sequential reactions that cleave the cruciform structures give rise to the translocation: GEN1-mediated resolution that cleaves diagonally at the four-way junction of the cruciform and Artemismediated opening of the subsequently formed hairpin ends. Indeed, translocation products in human sperm reveal the remnants of this two-step mechanism. These two intrinsic pathways that normally fulfil vital functions independently, Holliday-junction resolution in homologous recombination and coding joint formation in rearrangement of antigen-receptor genes, act upon the unusual DNA conformation in concert and lead to a subset of recurrent GCRs in humans.

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Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations

et al. 2013

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“…Molecular cloning of translocation breakpoints has identified similar palindromic sequences on partner chromosomes, such as 17q11, 4q35.1, 1p21.2, and 8q24.1. [12][13][14][15] Hence, palindrome-mediated chromosomal translocation is one of the common pathways of human genomic rearrangements.…”

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Prevalence of Emanuel syndrome: Theoretical frequency and surveillance result

Ohye

Inagaki

Kato

et al. 2014

Pediatrics International

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Constitutional t(11;22)(q23;q11) is the most frequent recurrent non-Robertsonian translocation in humans. Balanced carriers of t(11;22) usually manifest no clinical symptoms, and are often identified after the birth of offspring with an unbalanced form of this translocation, known as Emanuel syndrome. To determine the prevalence of the disorder, we sent surveillance questionnaires to 735 core hospitals in Japan. The observed number of Emanuel syndrome cases was 36 and that of t(11;22) balanced translocation carriers, 40. On the basis of the de novo t(11;22) translocation frequency in sperm from healthy men, we calculated the frequency of the translocations in the general population. Accordingly, the prevalence of Emanuel syndrome was estimated at 1 in 110 000. Based on this calculation, the estimated number of Emanuel syndrome cases in Japan is 1063 and of t(11;22) balanced translocation carriers, 16 604, which are much higher than the numbers calculated from the questionnaire responses. It is possible that this discordance is partly attributable to a lack of disease identification. Further efforts should be made to increase the awareness of Emanuel syndrome to ensure a better quality of life for affected patients and their families.

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“…This analysis did not identify copy number alterations at either 3p14 in the FRA3B region or at the chromosome 8 breakpoint region (Supplementary Figure 3). Thus, as is the case with other PATRR-mediated translocations, the t(3;8)s appear to be balanced translocations that do not result in a gain or loss of genetic material (14, 15, 36). …”

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confidence: 83%

“…Genomic DNA was extracted from semen or testis samples and translocation-specific PCRs were performed as above. Primers for detection of PATRR-mediated translocations have been previously described and are listed in Table 1 (15, 32). Multiple batches of 100ng sperm DNA each containing 33,000 haploids were amplified.…”

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confidence: 99%

“…The presence of PATRRs at 22q11, as well as within the relevant 11q23, 8q24 and 17q11 regions, suggests a PATRR-mediated etiology for these recurrent constitutional translocations with 22q11. These translocations have been reported in unrelated families and the breakpoints in almost all translocation carriers are localized at the center of the PATRR on both chromosomes (10–15). Similarly, a t(1;22)(q21;q11), t(9;22)(p21;q11) and a t(4;22)(q35;q11), all non-recurrent translocations, were reported as PATRR mediated (16–18).…”

Section: Introductionmentioning

confidence: 95%

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Analysis of the t(3;8) of hereditary renal cell carcinoma: a palindrome-mediated translocation

et al. 2014

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It has emerged that palindrome-mediated genomic instability generates DNA-based rearrangements. The presence of palindromic AT-rich repeats (PATRRs) at the translocation breakpoints suggested a palindrome-mediated mechanism in the generation of several recurrent constitutional rearrangements: the t(11;22), t(17;22) and t(8;22). To date, all reported PATRR mediated translocations include the PATRR on chromosome 22 (PATRR22) as a translocation partner. Here, the constitutional rearrangement, t(3;8)(p14.2;q24.1), segregating with renal cell carcinoma in two families, is examined. The chromosome 8 breakpoint lies in PATRR8 in the first intron of the RNF139 (TRC8) gene while the chromosome 3 breakpoint is located in an AT-rich palindromic sequence in intron 3 of the FHIT gene (PATRR3). Thus, the t(3;8) is the first PATRR-mediated, recurrent, constitutional translocation that does not involve PATRR22. Furthermore, similar to the t(11;22) and t(8;22), we detect de novo translocations involving PATRR3 in normal sperm. The breakpoint on chromosome 3 is in proximity to FRA3B, the most common fragile site in the human genome and a site of frequent deletions in tumor cells. However, the lack of involvement of PATRR3 sequence in numerous FRA3B-related deletions suggests that there are several different DNA sequence based etiologies responsible for chromosome 3p14.2 genomic rearrangements.

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A Palindrome-Mediated Recurrent Translocation with 3:1 Meiotic Nondisjunction: The t(8;22)(q24.13;q11.21)

Cited by 45 publications

References 44 publications

Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations

Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations

Prevalence of Emanuel syndrome: Theoretical frequency and surveillance result

Analysis of the t(3;8) of hereditary renal cell carcinoma: a palindrome-mediated translocation

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