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

Myotonic dystrophy (DM) is the most prevalent inherited neuromuscular disea se 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 patte rns. 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 mR NA reading frame, occur as independent stochastic events in all tissues exa mined, In contrast, the excision of exons 13/14 that causes a frameshift an d creates a C-terminally truncated protein is clearly cell type dependent a nd occurs predominantly in smooth muscle. We generated all six full-length mouse cDNAs that result from combinations of these three major splicing eve nts and show that their transfection into cells in culture leads to product ion of four different similar to 74 kDa full-length (heart-, skeletal muscl e- or brain-specific) and two C-terminally truncated similar to 68 kDa (smo oth 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.