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

Myotonic dystrophy protein kinase (DMPK) is a member of the AGC super family of serine/threonine protein kinases (Caenepeel et al., 2004; Manning et al., 2002). The DMPK human gene encodes several alternative spliced protein products believed to be involved in remodeling of the actin cytoskeleton, mitochondrial dynamics, ion homeostasis and nuclear envelope stability. DMPK and its isoforms are mainly expressed in skeletal, heart and smooth muscle, and brain, the main targets of myotonic dystrophy type 1 (DM1) (Groenen et al., 2000; Ueda et al., 2000). DM1 is the most common form of muscular dystrophy in adults with a frequency of 1 in 8,000 individuals worldwide. It is a multisystem dominantly inherited disorder characterized by myotonia, progressive muscular weakness and wasting, cardiac defects, cataracts and frontal balding, as well as several central nervous system (CNS) manifestations (Harper et al., 2002). The disease is caused by the expansion of an unstable (CTG)n repeat in the 3’-untranslated region (3’-UTR) of the DMPK gene (Brook et al., 1992; Fu et al., 1992; Mahadevan, M. et al., 1992). In healthy population the CTG tract is polymorphic with alleles ranging from 5 to 37 in length. Individuals carrying the DM1 premutation, a tract between 38 and 49 CTG repeats, generally are asymptomatic but are at risk of transmitting a pathological expanded mutation. In contrast, a CTG expansion between 50 and 4000 CTG repeats results in DM1 disease. Affected families show the phenomenon of anticipation; longer expansions correlate with an earlier age of onset and more severe course in subsequent generations. Based on their clinical presentation DM1 is classified into four subtypes: late onset, classic DM1, childhood onset and congenital DM1 (CDM) (Harley et al., 1992). An RNA-mediated dominant gain-of-function is currently accepted as the pathogenic mechanism to explain features of the DM1. DMPK toxic transcripts accumulate as nuclear foci (Davis et al., 1997; Taneja et al., 1995), interfering with the activity of RNA-interacting proteins and altering RNA metabolism, notably the splicing programme (Ranum & Day, 2004). Although reduced DMPK protein levels in DM1 tissues