Lcrmediated Somatic Nf1 Microdeletions

An estimated 25% of NF1 microdeletions occur as postzygotic mutations during mitosis resulting in tissue mosaicism (21) and a phenotype that can vary from the classical generalized

Recurrent mitotic 1.2 Mb NF1 microdeletions

Recurrent mitotic 1.2 Mb NF1 microdeletions

Fig. 5. Recurrent mitotic NF1 microdeletions. The schematic shows the pair of JJAZ1 low-copy repeats (LCRs) that mediate recurrent mitotic microdeletions of the NF1 region (refer to Fig. 1 for genomic context of the region). These LCRs share 46 kb of homology with 97% sequence identity and are located just "internal" to the NF1-REP-P1 and -M (26). Breakpoints are drawn for four cases of 1.2-Mb deletions mediated by paralogous recombination between the JJAZ1-Y pseudogene and the JAZZ1 functional gene. (Three from ref. 21 and UWA186-1 as an additional unpublished case from my laboratory.)

Fig. 5. Recurrent mitotic NF1 microdeletions. The schematic shows the pair of JJAZ1 low-copy repeats (LCRs) that mediate recurrent mitotic microdeletions of the NF1 region (refer to Fig. 1 for genomic context of the region). These LCRs share 46 kb of homology with 97% sequence identity and are located just "internal" to the NF1-REP-P1 and -M (26). Breakpoints are drawn for four cases of 1.2-Mb deletions mediated by paralogous recombination between the JJAZ1-Y pseudogene and the JAZZ1 functional gene. (Three from ref. 21 and UWA186-1 as an additional unpublished case from my laboratory.)

NF1 to localized or segmental NF1 (37,38). Like the common recurrent meiotic NF1 microdeletions, somatic rearrangements occur by paralogous recombination; however, the site of preferential exchange was different. Seven of eight mitotic NF1 microdeletions had breakpoints that clustered at the JJAZ1-y pseudogene and the JJAZ1 functional gene, which are direct repeats located adjacent and NF1-REP-P1 and NF1-REP-M (Fig. 1) (21). The JJAZ1-Y has 9 exons that share 46-kb homology at 97% identity with the functional JJAZ1 gene (Fig.5) (26). In three cases, breakpoint intervals were mapped at the nucleotide level by use of PSVs and the microdeletions occurred at different sites (Fig. 5). Consistent with this observation is the breakpoint of a somatic mosaic female patient in my laboratory, UWA186-1, whose breakpoint in intron 8 is approx 2 kb proximal to that of SB-B9 (Stephens, unpublished observations). The JJAZ1-y/JJAZ1 fusion product of the recombination is expressed in human-rodent somatic cell lines, but unlikely to be translated owing to stop codons in the pseudogene (21).

The level of somatic mosaicism for JJAZ1 -mediated NF1 microdeletions varied significantly in different patient tissues. The percentage of deleted cells as determined by FISH was quite high in peripheral blood (91-100%) and significantly lower in buccal cells or skin fibroblasts (51-59%) (21). These data suggest that a selective growth advantage of hematopoetic stem cells carrying NF1 microdeletions. Different levels of mosaicism significantly compound both the diagnosis and counseling of patients with JJAZ1 -mediated mosaic NF1 microdeletions.

JJAZ1- and NF1-REP-mediated NF1 microdeletions have striking differences and parallels. First, paralogous recombination at JJAZ1 LCRs is preferentially mitotic, whereas that at NF1-REP LCRs is meiotic. Second, JJAZ1 paralogous recombination is intrachromosomal in two cases examined (21), whereas NF1-REP paralogous recombination is primarily interchro-mosomal (16). Third, small inverted repeats of75-127 bp flank the intronic JJAZ1 breakpoints in two cases and may cause double strand breaks by forming hairpins (21). Parallels between the two types of microdeletions include paralogous recombination, and deletion of the same set of contiguous genes, except for the functional KIAA0563-rel gene near NF1-REP-M, which is not deleted in JJAZ1 -mediated rearrangements (Fig. 1). Furthermore, both paralogous recombination events occur preferentially in females for reasons that are not known (15,17,21).

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