Co-localisation of CCG repeats and chromosome deletion breakpoints in Jacobsen syndrome: evidence for a common mechanism of chromosome breakage

Abstract

Folate-sensitive fragile sites are associated with the expansion and hypermethylation of CCG-repeats. The fragile site in 11q23.3, FRA11B, has been shown to cause chromosome deletions in vivo, its expression being associated with Jacobsen (11q-) syndrome. However, the majority of Jacobsen deletions are distal to FRA11B and are not related to its expression. To test the hypothesis that other unidentified fragile sites might be located in 11q23.3-24 and may cause these deletions, we have identified and characterised CCG-trinucleotide repeats within a 40 Mb YAC contig spanning distal chromosome 11q. Only eight CCG-repeats were identified within the entire YAC contig (not including FRA11B ), six of which map to the region of 11q23.3-24 that includes Jacobsen deletions. We have previously collated the deletion mapping data of 24 Jacobsen patients with the physical map of chromosome 11q, and accurately localised six breakpoints to short intervals corresponding to individual YAC clones. We now show that in each of these cases, YAC clones found to contain a deletion breakpoint also contain a CCG-repeat. The improved analysis of one of these deletions, together with those of several new Jacobsen cases, further strengthens this association by localising five breakpoints to individual PAC clones containing CCG-repeats. These data provide strong evidence for the non-random clustering of chromosome deletion breakpoints with CCG-repeats, and suggests that they may play an important role in a common mechanism of chromosome breakage.

Role for CCG-trinucleotide repeats in the pathogenesis of chronic lymphocytic leukemia

“…We have also recently mapped the breakpoint of a patient with Jacobsen syndrome to the same repeat. 39 A further CCG repeat (TNR/11q#6) was located within PAC dJ36-N10 less than 1 Mb from the repeat TNR/11q#7.…”

“…39 Nine overlapping YACs (y986C07, y984E06, y891F09, y952H06, y921B11, y795F05, y975H06, y793D09, y920C04), located within the CLL minimal deleted region, were found to contain the same trinucleotide repeat. The high density of microsatellite markers in this region of the YAC contig allowed the accurate localization of this CCG-repeat to between D11S1897 and D11S2105.…”

“…The breakpoint regions corresponded to those previously observed in Jacobsen syndrome. 39 The mechanism of breakage in Jacobsen syndrome has been shown to directly relate to CCG repeats (eg, FRA11B). 34 The effect of a trinucleotide repeat (chromosome breakage and deletion) may be manifested a number of kilobases away from the location of the repeat sequence (eg, fragile X syndrome 43 and Jacobsen syndrome 34 ).…”

“…Southern hybridization may not demonstrate a rearrangement because of the distance away from the breakpoint region. PACs from regions flanking CCG repeats 39 were applied as probes in dual-color metaphase FISH to further refine the deletion mapping and to determine a possible involvement for CCG repeats in chromosome breakage (Figure 1).…”

Epigenetics, fragile X syndrome and transcriptional therapy

“…In fact, the expanded and hypermethylated CGG sequence is replicating so late that (under particular culture conditions) it is not duplicated at mitosis and cannot condense at metaphase. All these fragile sites (including FRAXA, FRAXE, FRAXF, FRA10A, FRA11A, FRA11B, FRA12A, and FRA16A) are located in promoters and their expression associates with silencing of the respective genes [Oberlé et al, 1991;Knight et al, 1993;Ritchie et al, 1994;Nancarrow et al, 1995;Jones et al, 2000;Sarafidou et al, 2004;Debacker et al, 2007;Winnepenninckx et al, 2007]. …”