Splice-mediated insertion of an Alu sequence inactivates ornithine aminotransferase: A role for Alu elements in human mutation

In studies of mutations causing deficiency of ornithine δ-aminotransferase (EC 2.6.1.13), we found an allele whose mature mRNA has a 142-nucleotide insertion at the junction of sequences from exons 3 and 4. The insert derives from an Alu element in ornithine 5-aminotransferase intron 3 oriented in the direction opposite to transcription (an "anti-sense Alu"). A guanine → cytosine transversion creates a donor splice site in this Alu, activating a cryptic acceptor splice site at its 5′ end and causing splice-mediated insertion of an Alu fragment into the mature ornithine-δ-aminotransferase mRNA. We note that the complement of the Alu consensus sequence has at least two cryptic acceptor sites and several potential donor sequences and predict that similar mutations will be found in other genes.