title: Pathogenic orphan transduction created by a nonreference LINE-1 retrotransposon.
abstract: Long INterspersed Element-1 (LINE-1) retrotransposons comprise 17% of the human genome, and move by a potentially mutagenic "copy and paste" mechanism via an RNA intermediate. Recently, the retrotransposition-mediated insertion of a new transcript was described as a novel cause of genetic disease, Duchenne muscular dystrophy, in a Japanese male. The inserted sequence was presumed to derive from a single-copy, noncoding RNA transcribed from chromosome 11q22.3 that retrotransposed into the dystrophin gene. Here, we demonstrate that a nonreference full-length LINE-1 is situated in the proband and maternal genome at chromosome 11q22.3, directly upstream of the sequence, whose copy was inserted into the dystrophin gene. This LINE-1 is highly active in a cell culture assay. LINE-1 insertions are often associated with 3' transduction of adjacent genomic sequences. Thus, the likely explanation for the mutagenic insertion is a LINE-1-mediated 3' transduction with severe 5' truncation. This is the first example of LINE-1-induced human disease caused by an "orphan" 3' transduction.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Szilvia
authors.initials: S
authors.lastname: Solyom
authors.forename: Adam D
authors.initials: AD
authors.lastname: Ewing
authors.forename: Dustin C
authors.initials: DC
authors.lastname: Hancks
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeshima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Awano
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
authors.forename: Haig H
authors.initials: HH
authors.lastname: Kazazian
mesh_terms: D002880:Chromosomes, Human, Pair 11; D016189:Dystrophin / Q000235:genetics; D023061:Gene Order; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics; D016254:Mutagenesis, Insertional
chemical_list: D016189:Dystrophin
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