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. Hum Mutat 33:369–371, 2012.