Localization of Jacobsen Syndrome Breakpoints on a 40-Mb Physical Map of Distal Chromosome 11q

Abstract

Jacobsen syndrome is a haploinsufficiency disorder caused, most frequently by terminal deletion of part of the long arm of chromosome 11, with breakpoints in 11q23.3–11q24.2. Inheritance of an expanded p(CCG)n trinucleotide repeat at the folate-sensitive fragile site FRA11B has been implicated in the generation of the chromosome breakpoint in several Jacobsen syndrome patients. The majority of such breakpoints, however, map distal to this fragile site and are not linked with its expression. To characterize these distal breakpoints and ultimately to further investigate the mechanisms of chromosome breakage, a 40-Mb YAC contig covering the distal long arm of chromosome 11 was assembled. The utility of the YAC contig was demonstrated in three ways: (1) by rapidly mapping the breakpoints from two new Jacobsen syndrome patients using FISH; (2) by demonstrating conversion to high resolution PAC contigs after direct screening of PAC library filters with a YAC clone containing a Jacobsen syndrome breakpoint; and (3) by placing 23 Jacobsen syndrome breakpoints on the physical map. This analysis has suggested the existence of at least two new Jacobsen syndrome breakpoint cluster regions in distal chromosome 11.

Fragile sites, chromosomal lesions, tandem repeats, and disease

“…Most of the FMR1 deletions/rearrangements are covered in Figures 8A–D ( see citations therein). Breakpoints that frequently occur at RFSs, particularly under replicative stress, tend to map to regions surrounding the expanded repeat motif, such as at FRAXA ( Warren et al, 1987 ; Oberlé et al, 1991 ; Dobkin et al, 2009 ; Verdyck et al, 2015 ) and FRA11B ( Michaelis et al, 1998 ; Tunnacliffe et al, 1999 ). Translocations, deletions, and rearrangements at the fragile X chromosome as well as chromosome 3 were induced under replicative stress using aphidicolin or FUdR, respectively, in somatic cell hybrids ( Glover and Stein, 1988 ).…”

“…The molecular basis of the deletions is the fragile site FRA11B (CGG)n repeat expansion, which upon transmission can result in breakpoints of the chromosome ( Voullaire et al, 1987 ; Jones et al, 1995 ). These breakpoints frequently occur within the vicinity of RFS but can also occur up to 10 Mb away from the (CGG)n repeat ( Michaelis et al, 1998 ; Tunnacliffe et al, 1999 ). This fragile site was the first established as causing in vivo breakage and disease manifestation, demonstrating the clinical importance of fragile sites.…”