A new exon created by intronic insertion of a rearranged LINE-1 element asthe cause of chronic granulomatous disease

Long interspersed nuclear element-1 (LINE-1) or L1 elements are DNA element s present in the genome in high copy number and capable of active retrotran sposition. Here we present a patient with severe chronic granulomatous dise ase (CCD) caused by insertion of an L1 sequence into intron 5 of the X-line d gene CYBB. Due to internal rearrangements, the insert introduced new spli ce sites into the intron. This resulted in a highly heterogeneous splicing pattern with introduction of two L1 fragments as new exons into the transcr ipts and concomitant skipping of exonic coding sequence. Because no wild-ty pe cDNA was found, this mechanism is probably responsible for the patient's phenotype. The L1 fragment, which belongs to the Ta subset of transcriptio nally active LINEs, illustrates a new mechanism by which these elements can modify the transcribed coding sequence of genes.