Constitutive and regulated modes of splicing produce six major myotonic dystrophy protein kinase (DMPK) isoforms with...

Myotonic dystrophy (DM) is the most prevalent inherited neuromuscular disease in adults. The genetic defect is a CTG triplet repeat expansion in the 3'-untranslated region of the myotonic dystrophy protein kinase ( DMPK ) gene, consisting of 15 exons. Using a transgenic DMPK-overexpressor mouse model, we demonstrate here that the endogenous mouse DMPK gene and the human DMPK transgene produce six major alternatively spliced mRNAs which have almost identical cell type-dependent distribution frequencies and expression patterns. Use of a cryptic 5' splice site in exon 8, which results in absence or presence of 15 nucleotides specifying a VSGGG peptide motif, and/or use of a cryptic 3' splice site in exon 14, which leads to a frameshift in the mRNA reading frame, occur as independent stochastic events in all tissues examined. In contrast, the excision of exons 13/14 that causes a frameshift and creates a C-terminally truncated protein is clearly cell type dependent and occurs predominantly in smooth muscle. We generated all six full-length mouse cDNAs that result from combinations of these three major splicing events and show that their transfection into cells in culture leads to production of four different approximately 74 kDa full-length (heart-, skeletal muscle- or brain-specific) and two C-terminally truncated approximately 68 kDa (smooth muscle-specific) isoforms. Information on DMPK mRNA and protein isoform expression patterns will be useful for recognizing differential effects of (CTG)(n)expansion in DM manifestation.