A de novo Alu insertion results in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with a high mutation rate and variable expression, characterized by neurofibromas, café-au-lait spots, Lisch nodules of the iris, and less frequent features including bone deformities and learning disabilities. The recently cloned NF1 gene encodes a transcript of 13 kilobases from a ubiquitously expressed locus on chromosome 17. Most NF1 patients are expected to have unique mutations, but only a few have so far been characterized, restricting genetic and functional information and the design of DNA diagnostics. We report an unusual NF1 mutation, that of a de novo Alu repetitive element insertion into an intron, which results in deletion of the downstream exon during splicing and consequently shifts the reading frame. This previously undescribed mechanism of mutation indicates that Alu retrotransposition is an ongoing process in the human germ line.