A NOVEL ALU-LIKE ELEMENT REARRANGED IN THE DYSTROPHIN GENE CAUSES A SPLICING MUTATION IN A FAMILY WITH X-LINKED DILATED CARDIOMYOPATHY

We have identified and characterized a genomic sequence with some feat ures typical of Alu-like mobile elements rearranged into the dystrophi n gene in a family affected by X-linked dilated cardiomyopathy. The Al u-like sequence rearrangement occurred 2.4 kb downstream from the 5' e nd of intron 11 of the dystrophin gene. This rearrangement activated o ne cryptic splice site in intron 11 and produced an alternative transc ript containing the Alu-like sequence and part of the adjacent Intron la, spliced between exons 11 and 12. Translation of this alternative t ranscript is truncated because of the numerous stop codons present in every frame of the Alu-like sequence. Only the mutant mRNA was detecte d in the heart muscle, but in the skeletal muscle it coexisted with th e normal one. This result is supported by the immunocytochemical findi ngs, which failed to detect dystrophin in the patient's cardiac muscle but showed expression of a reduced level of protein in the skeletal m uscle. Comparative analysis of the Alu-like sequence showed high homol ogy with other repeated-element-containing regions and with several ex pressed sequence tags. We suggest that this Alu-like sequence could re present a novel class of repetitive elements, reiterated and clustered with some known mobile elements-and capable of transposition. Our rep ort underlines the complexity of the pathogenic mechanism leading to X -linked dilated cardiomyopathy but suggests that differences in tissue -specific expression of dystrophin mutations may be a common feature i n this condition.