DMPK protein isoforms are differentially expressed in myogenic and neural cell lineages

Abstract

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by an unstable (CTG . CAG)n segment in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. It is commonly accepted that DMPK mRNA-based toxicity is the main contributor to DM1 manifestations; however, not much is known about the significance of the DMPK protein. To appreciate its normal and possible pathobiological role, we analyzed the patterns of DMPK splice isoform expression in mouse tissues. Long membrane-anchored DMPK dominated in heart, diaphragm, and skeletal muscle, whereas short cytosolic isoforms were highly expressed in bladder and stomach. Both isoform types were present in diverse brain regions. DMPK protein was also detectable in cultured myoblasts, myotubes, cortical astrocytes, and related cell lines of neural or muscle origin, but not in hippocampal neurons. This work identifies DMPK as a kinase with pronounced expression in diverse muscle and neural tissues that are affected in DM1.

Myotonic Dystrophy Protein Kinase: Structure, Function and Its Possible Role in the Pathogenesis of Myotonic Dystrophy Type 1

“…DMPK at protein level has also been identified in several brain regions (van der Ven et al, 1993) both in neurons and glia. Interestingly astrocytes from brain cortex show higher DMPK levels compared with neurons (Oude Ophuis et al, 2009a). DMPK transcripts and protein products are also detected in fetal eyes, adult retina, corneal epithelia and optic nerve (Winchester et al, 1999).…”

“…Interestingly, both longand short-isoforms are expressed in diverse brain regions (Oude Ophuis et al, 2009a). Other reports have demonstrated that the four different ~74-kDa full-length DMPK isoforms are present in heart, skeletal muscle and brain, in contrast to the two C-terminally truncated ~68-kDa isoforms that are restricted to smooth muscle and to a lesser extent at heart (Groenen et al, 2000).…”

“…In DMPK -/-mice myoblasts, exogenous expression of the cytosolic DMPK E isoform results in the presence of stress fibers, significant changes in myoblast polarity and delay myogenesis progression (Mulders et al, 2011). It is known that DMPK gene is expressed early in muscle development, but alternative splicing down-regulates DMPK E expression during myogenesis (Jansen et al, 1996;Oude Ophuis et al, 2009a). In contrast, membrane-anchored DMPK splice isoforms remain equally abundant between myoblast and myotubes, indicating that expression of these isoforms is not differentially regulated during myogenesis.…”

“…With respect to DMPK, it was recently demonstrated that both long and short DMPK isoforms are expressed across many brain regions, including brainstem, olfactory bulb, and striatum. In addition, DMPK protein was identified in astrocytes and U373 glioblastoma cells (Oude Ophuis et al, 2009a). Therefore, involvement of DMPK isoforms in DM1-mediated mental retardation can not be ruled out.…”

“…Studies focused on the biology of this protein had received little attention, as protein product of DMPK gene seemed to have no direct role in the disease. Identification of novel DMPK targets, and comparative differences of DMPK isoforms have started to emerge (Groenen et al, 2000;Kaliman & Llagostera, 2008;Mulders et al, 2011;Oude Ophuis et al, 2009a;van Herpen et al, 2005). This chapter offers the current knowledge about the structure, expression patterns and function of DMPK and its isoforms.…”