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Pure intronic rearrangements leading to aberrant pseudoexon inclusion in dystrophinopathy: a new class of mutations?
Author(s) -
Khelifi Mouna Messaoud,
Ishmukhametova Aliya,
Van Kien Philippe Khau,
Thorel Delphine,
Méchin Déborah,
Perelman Serge,
Pouget Jean,
Claustres Mireille,
TufferyGiraud Sylvie
Publication year - 2011
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.21471
Subject(s) - biology , intron , genetics , exon , rna splicing , gene , phenotype , microbiology and biotechnology , rna
We report on two unprecedented cases of pseudoexon (PE) activation in the DMD gene resulting from pure intronic double‐deletion events that possibly involve microhomology‐mediated mechanisms. Array comparative genomic hybridization analysis and direct genomic sequencing allowed us to elucidate the causes of the pathological PE inclusion detected in the RNA of the patients. In the first case (Duchenne phenotype), we showed that the inserted 387‐bp PE was originated from an inverted ∼57 kb genomic region of intron 44 flanked by two deleted ∼52 kb and ∼1 kb segments. In the second case (Becker phenotype), we identified in intron 56 two small deletions of 592 bp (del 1) and 29 bp (del 2) directly flanking a 166‐bp PE located in very close proximity (134 bp) to exon 57. The key role of del 1 in PE activation was established by using splicing reporter minigenes. However, the analysis of mutant constructs failed to identify cis elements that regulate the inclusion of the PE and suggested that other splicing regulatory factors may be involved such as RNA structure. Our study introduces a new class of mutations in the DMD gene and emphasizes the potential role of underdetected intronic rearrangements in human diseases. Hum Mutat 32:1–9, 2011. © 2011 Wiley‐Liss, Inc.