The constitutional t(17;22): another translocation mediated by palindromic AT-rich repeats

Abstract

We have demonstrated that the breakpoints of the constitutional t(11;22) are located at palindromic AT-rich repeats (PATRRs) on 11q23 and 22q11. As a mechanism for this recurrent translocation, we proposed that the PATRR forms a cruciform structure that induces the genomic instability leading to the rearrangement. A patient with neurofibromatosis type 1 (NF1) had previously been found to have a constitutional t(17;22) disrupting the NF1 gene on 17q11. We have localized the breakpoint on 22q11 within the 22q11-specific low-copy repeat where the breakpoints of the constitutional t(11;22)s reside, implying a similar palindrome-mediated mechanism for generation of the t(17;22). The NF1 gene contains a 195-bp PATRR within intron 31. We have isolated the junction fragments from both the der(17) and the der(22). The breakpoint on 17q11 is close to the center of the PATRR. A published breakpoint of an additional NF1-afflicted patient with a constitutional t(17;22) is also located close to the center of the same PATRR. Our data lend additional support to the hypothesis that PATRR-mediated genomic instability can lead to a variety of translocations.

Figure 1

Localization of the 22q11 breakpoint of the patient with t(17;22). A, Map of the 22q11 breakpoint region. LCR-22s are indicated by boxes. Location of probes used for FISH analysis are indicated by the vertical bars. B, FISH results on metaphase chromosomes of the t(17;22) patient. Both c68a1 (N41, red) and c87f9 (ZNF74, green) are hybridized simultaneously to metaphase chromosomes. As a control, cos82 (22q13, red) was used to mark distal 22q. Signals for c87f9 and cos82 are observed on the der(17) (arrow), whereas the c68a1 signal is observed remaining on the der(22) (arrow head). This indicates that the breakpoint is located between these markers in LCR22B. The other chromosome with signal for all three probes is the normal chromosome 22.

Figure 2

The chromosome 17 PATRR. A, The PATRR is located 209 bp downstream of exon 31 within the NF1 gene. B, Genomic sequence of intron 31. Exonic sequence is displayed in italics. The 195-bp PATRR is shown in bold. PCR primers used for this study are underlined. C, Sequence comparison of the proximal and distal arms of the PATRR by ClustalW. Asterisks indicate identical nucleotides between the proximal and distal arms. Thick arrows indicate the breakpoints of the patient with t(17;22), whereas thin arrows indicate that of the patient described by Kehrer-Sawatski et al. (1997).

Figure 3

Junction fragments of the t(17;22). A, Structure of the junction fragments of the der(17) and the der(22). White boxes indicate chromosome 17, and gray boxes indicate chromosome 22. PCR primers are indicated by arrows. B, Sequence of the junction fragments. Each sequence is shown from chromosome 17 to chromosome 22. Chromosome-17 PATRR is indicated by boldface, whereas chromosome 22 PATRR is indicated by italics. PCR primers are underlined.