A MUTATION IN THE DYSTROPHIN GENE SELECTIVELY AFFECTING DYSTROPHIN EXPRESSION IN THE HEART

We have previously shown in a large X-linked pedigree that a deletion removing the dystrophin muscle promoter, the first muscle exon and par t of intron 1 caused a severe dilated cardiomyopathy with no associate d muscle weakness, Dystrophin expression was present in the muscle of affected males and transcription studies indicated that this dystrophi n originated from the brain and Purkinje cell isoforms, upregulated in this skeletal muscle, We have now studied dystrophin transcription an d expression in the heart of one member of this family, In contrast to the skeletal muscle, dystrophin transcription and expression were abs ent in the heart, with the exception of the distal Dp71 dystrophin iso form, normally present in the heart, The 43- and 50-kD dystrophin-asso ciated proteins were severely reduced in the heart, despite the presen ce of Dp71, but not in skeletal muscle, The absence of dystrophin and the down-regulation of the dystrophin-associated proteins in the heart accounted for the severe cardiomyopathy in this family, The mutation present in these males selectively affects dystrophin expression in th e heart; this could be secondary to the removal of cardiac-specific re gulatory sequences, This family may represent the first example of a m utation specifically affecting the cardiac expression of a gene, prese nt physiologically in both the skeletal and cardiac muscles.