Open AccessA birth of bipartite exon by intragenic deletion
Author(s) -
Nozu Kandai,
Iijima Kazumoto,
Igarashi Toru,
Yamada Shiro,
Kralovicova Jana,
Nozu Yoshimi,
Yamamura Tomohiko,
Minamikawa Shogo,
Morioka Ichiro,
Ninchoji Takeshi,
Kaito Hiroshi,
Nakanishi Koichi,
Vorechovsky Igor
Publication year - 2017
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.277
Subject(s) - exon , splice site mutation , genetics , intron , biology , rna splicing , splice , exon skipping , polypyrimidine tract , exon trapping , exon shuffling , retrotransposon , exonic splicing enhancer , tandem exon duplication , alternative splicing , gene , transposable element , rna , genome
Abstract Background Disease‐causing mutations that activate transposon‐derived exons without creating a new splice‐site consensus have been reported rarely, but they provided unique insights into our understanding of structural motifs required for inclusion of intronic sequences in mature transcripts. Methods We employ a combination of experimental and computational techniques to characterize the first de novo bipartite exon activation in genetic disease. Results The exon originated from two separate introns as a result of an in‐frame COL 4A5 deletion associated with a typical Alport syndrome. The deletion encompassed exons 38 through 41 and activated a cryptic 3′ and 5′ splice site that were derived from intron 37 and intron 41, respectively. The deletion breakpoint was in the middle of the new exon, with considerable complementarity between the two exonic parts, potentially bringing the cryptic 3′ and 5′ splice site into proximity. The 3′ splice site, polypyrimidine tract and the branch site of the new exon were derived from an inactive, 5′ truncated LINE ‐1 retrotransposon. This ancient LINE ‐1 copy sustained a series of mutations that created the highly conserved AG dinucleotide at the 3′ splice site early in primate development. The exon was fully included in mature transcripts and introduced a stop codon in the shortened COL 4A5 mRNA , illustrating pitfalls of inferring disease severity from DNA mutation alone. Conclusion These results expand the repertoire of mutational mechanisms that alter RNA processing in genetic disease and illustrate the extraordinary versatility of transposed elements in shaping the new exon‐intron structure and the phenotypic variability.