TY - JOUR
T1 - Gross genomic rearrangements involving deletions in the CFTR gene
T2 - characterization of six new events from a large cohort of hitherto unidentified cystic fibrosis chromosomes and meta-analysis of the underlying mechanisms
AU - Férec, Claude
AU - Casals, Teresa
AU - Chuzhanova, Nadia
AU - Macek, Milan
AU - Bienvenu, Thierry
AU - Holubova, Andrea
AU - King, Caitriona
AU - McDevitt, Trudi
AU - Castellani, Carlo
AU - Farrell, Philip M.
AU - Sheridan, Molly
AU - Pantaleo, Sarah Jane
AU - Loumi, Ourida
AU - Messaoud, Taieb
AU - Cuppens, Harry
AU - Torricelli, Francesca
AU - Cutting, Garry R.
AU - Williamson, Robert
AU - Ramos, Maria Jesus Alonso
AU - Pignatti, Pier Franco
AU - Raguénès, Odile
AU - Cooper, David N.
AU - Audrézet, Marie Pierre
AU - Chen, Jian Min
N1 - Funding Information:
JM Chen is a visiting Professor of Genetics supported by the Ministère de la Jeunesse, de l’Éducation Nationale et de la Recherche, France. This work was supported by the INSERM (Institut National de la Santé et de la Recherche Médicale) and the VLM (Vaincre La Mucoviscidose), France; the Grant FIS/FEDER PI020099 (to T Casals); and the grant VZ FNM 00064203 (to M Macek).
PY - 2006/5
Y1 - 2006/5
N2 - Gross genomic rearrangements involving deletions in the CFTR gene have recently been found to account for ∼20 of unidentified cystic fibrosis (CF) chromosomes in both French and Italian patients. Using QMPSF and walking quantitative DHPLC, six novel mutations (three simple deletions, two complex deletions with short insertions of 3-6 bp, and a complex deletion with a 182 bp inverted downstream sequence) were characterized by screening 274 unidentified CF chromosomes from 10 different countries. These lesions increase the total number of fully characterized large CFTR genomic rearrangements involving deletions to 21. Systematic analysis of the 42 associated breakpoints indicated that all 21 events were caused by nonhomologous recombination. Whole gene complexity analysis revealed a significant correlation between regions of low sequence complexity and the locations of the deletion breakpoints. Known recombination-promoting motifs were noted in the vicinity of the breakpoints. A total of 11 simple deletions were potentially explicable in terms of the classical model of replication slippage. However, the complex deletions appear to have arisen via multiple mechanisms; three of the five complex deletions with short insertions and both examples of large inverted insertions (299 and 182 bp, respectively) can be explained by either a model of serial replication slippage in cis (SRScis) or SRS in trans (SRStrans). Finally, the nature and distribution of large genomic rearrangements in the CFTR gene were compared and contrasted with those of two other genes, DMD and MSH2, with a view to gaining a broader understanding of DNA sequence context in mediating the diverse underlying mutational mechanisms.
AB - Gross genomic rearrangements involving deletions in the CFTR gene have recently been found to account for ∼20 of unidentified cystic fibrosis (CF) chromosomes in both French and Italian patients. Using QMPSF and walking quantitative DHPLC, six novel mutations (three simple deletions, two complex deletions with short insertions of 3-6 bp, and a complex deletion with a 182 bp inverted downstream sequence) were characterized by screening 274 unidentified CF chromosomes from 10 different countries. These lesions increase the total number of fully characterized large CFTR genomic rearrangements involving deletions to 21. Systematic analysis of the 42 associated breakpoints indicated that all 21 events were caused by nonhomologous recombination. Whole gene complexity analysis revealed a significant correlation between regions of low sequence complexity and the locations of the deletion breakpoints. Known recombination-promoting motifs were noted in the vicinity of the breakpoints. A total of 11 simple deletions were potentially explicable in terms of the classical model of replication slippage. However, the complex deletions appear to have arisen via multiple mechanisms; three of the five complex deletions with short insertions and both examples of large inverted insertions (299 and 182 bp, respectively) can be explained by either a model of serial replication slippage in cis (SRScis) or SRS in trans (SRStrans). Finally, the nature and distribution of large genomic rearrangements in the CFTR gene were compared and contrasted with those of two other genes, DMD and MSH2, with a view to gaining a broader understanding of DNA sequence context in mediating the diverse underlying mutational mechanisms.
KW - Breakpoint
KW - CFTR
KW - Deletion
KW - Gross genomic rearrangements
KW - Mutation
KW - Mutational mechanisms
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U2 - 10.1038/sj.ejhg.5201590
DO - 10.1038/sj.ejhg.5201590
M3 - Article
C2 - 16493442
AN - SCOPUS:33646068392
SN - 1018-4813
VL - 14
SP - 567
EP - 576
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 5
ER -