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Palindrome‐Mediated and Replication‐Dependent Pathogenic Structural Rearrangements within the NF 1 Gene
Author(s) -
Hsiao MengChang,
Piotrowski Arkadiusz,
Alexander John,
Callens Tom,
Fu Chuanhua,
Mikhail Fady M.,
Claes Kathleen B.M.,
Messiaen Ludwine
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22569
Subject(s) - biology , breakpoint , genetics , chromosomal translocation , palindromic sequence , palindrome , gene rearrangement , gene , genome
Palindromic sequences can form hairpin structures or cruciform extrusions, which render them susceptible to genomic rearrangements. A 197‐bp long palindromic AT‐rich repeat ( PATRR 17) is located within intron 40 of the neurofibromatosis type 1 ( NF 1 ) gene (17q11.2). Through comprehensive NF 1 analysis, we identified six unrelated patients with a rearrangement involving intron 40 (five deletions and one reciprocal translocation t(14;17)(q32;q11.2)). We hypothesized that PATRR 17 may be involved in these rearrangements thereby causing NF 1. Breakpoint cloning revealed that PATRR 17 was indeed involved in all of the rearrangements. As microhomology was present at all breakpoint junctions of the deletions identified, and PATRR 17 partner breakpoints were located within 7.1 kb upstream of PATRR 17, fork stalling and template switching/microhomology‐mediated break‐induced replication was the most likely rearrangement mechanism. For the reciprocal translocation case, a 51 bp insertion at the translocation breakpoints mapped to a short sequence within PATRR 17, proximal to the breakpoint, suggesting a multiple stalling and rereplication process, in contrast to previous studies indicating a purely replication‐independent mechanism for PATRR ‐mediated translocations. In conclusion, we show evidence that PATRR 17 is a hotspot for pathogenic intragenic deletions within the NF 1 gene and suggest a novel replication‐dependent mechanism for PATRR ‐mediated translocation.