DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model

Myotonic dystrophy (DM) is the most common form of muscular dystrophy and i s caused by expansion of a CTG trinucleotide repeat on human chromosome 19. Patients with DM develop atrioventricular conduction disturbances, the pri ncipal cardiac manifestation of this disease. The etiology of the pathophys iological changes observed in DM has yet to be resolved. Haploinsufficiency of myotonic dystrophy protein kinase (DMPK), DM locus-associated homeodoma in protein (DMAHP) and/or titration of RNA-binding proteins by expanded CUG sequences have been hypothesized to underlie the multi-system defects obse rved in DM. Using an in vivo murine electrophysiology study, Re show that c ardiac conduction is exquisitely sensitive to DMPK gene dosage. DMPK-/- mic e develop cardiac conduction defects which include first-, second-, and thi rd-degree atrioventricular (A-V) block. Our results demonstrate that the A- V node and the His-Purkinje regions of the conduction system are specifical ly compromised by DMPK loss. Importantly, DMPK+/- mice develop first-degree heart block, a conduction defect strikingly similar to that observed in DM patients. These results demonstrate that DMPK dosage is a critical element modulating cardiac conduction integrity and conclusively link haploinsuffi ciency of DMPK with cardiac disease in myotonic dystrophy.