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Characterization of the nonallelic homologous recombination hotspot PRS3 associated with type-3 NF1 deletions.
Zickler, Antje M. 1,+; Hampp, Stephanie 1,+; Messiaen, Ludwine 2; Bengesser, Kathrin 1; Mussotter, Tanja 1; Roehl, Angelika C. 1; Wimmer, Katharina 3; Mautner, Victor-Felix 4; Kluwe, Lan 4,5; Upadhyaya, Meena 6; Pasmant, Eric 7; Chuzhanova, Nadia 8; Kestler, Hans A. 9; Hogel, Josef 1; Legius, Eric 10; Claes, Kathleen 11; Cooper, David N. 6; Kehrer-Sawatzki, Hildegard 1,*
[Article] Human Mutation. 33(2):372-383, February 2012.

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: Nonallelic homologous recombination (NAHR) is the major mechanism underlying recurrent genomic rearrangements, including the large deletions at 17q11.2 that cause neurofibromatosis type 1 (NF1). Here, we identify a novel NAHR hotspot, responsible for type-3 NF1 deletions that span 1.0 Mb. Breakpoint clustering within this 1-kb hotspot, termed PRS3, was noted in 10 of 11 known type-3 NF1 deletions. PRS3 is located within the LRRC37B pseudogene of the NF1-REPb and NF1-REPc low-copy repeats. In contrast to other previously characterized NAHR hotspots, PRS3 has not developed on a preexisting allelic homologous recombination hotspot. Furthermore, the variation pattern of PRS3 and its flanking regions is unusual since only NF1-REPc (and not NF1-REPb) is characterized by a high single nucleotide polymorphism (SNP) frequency, suggestive of unidirectional sequence transfer via nonallelic homologous gene conversion (NAHGC). By contrast, the previously described intense NAHR hotspots within the CMT1A-REPs, and the PRS1 and PRS2 hotspots underlying type-1 NF1 deletions, experience frequent bidirectional sequence transfer. PRS3 within NF1-REPc was also found to be involved in NAHGC with the LRRC37B gene, the progenitor locus of the LRRC37B-P duplicons, as indicated by the presence of shared SNPs between these loci. PRS3 therefore represents a weak (and probably evolutionarily rather young) NAHR hotspot with unique properties. Hum Mutat 33:372-383, 2012. (C) 2011 Wiley Periodicals, Inc.