Pathogenic orphan transduction created by a nonreference LINE-1 retrotransposon

Authors

  • Szilvia Solyom,

    1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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    • These authors contributed equally to this work and should be considered joint first authors.

  • Adam D. Ewing,

    1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. Present address: Center for Biomolecular Science and Engineering, University of California at Santa Cruz, Santa Cruz, California
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    • These authors contributed equally to this work and should be considered joint first authors.

  • Dustin C. Hancks,

    1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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    • These authors contributed equally to this work and should be considered joint first authors.

  • Yasuhiro Takeshima,

    1. Department of Pediatrics, Graduate School of Medicine, Kobe University, 7-5-1 Kusunokicho, Chuo, Kobe, Japan
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  • Hiroyuki Awano,

    1. Department of Pediatrics, Graduate School of Medicine, Kobe University, 7-5-1 Kusunokicho, Chuo, Kobe, Japan
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  • Masafumi Matsuo,

    1. Department of Pediatrics, Graduate School of Medicine, Kobe University, 7-5-1 Kusunokicho, Chuo, Kobe, Japan
    2. Present address: Department of Medical Rehabilitation, Faculty of Rehabilitation, Kobegakuin University, Ikawadani-cho, Nishi-ku, Kobe, Japan
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  • Haig H. Kazazian Jr

    Corresponding author
    1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • Johns Hopkins University School of Medicine, Broadway Research Building, Room 439, 733 N. Broadway, Baltimore, MD 21205.

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  • Communicated by Mark H. Paalman

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. Hum Mutat 33:369–371, 2012. © 2011 Wiley Periodicals, Inc.

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