title: Characterization of cardiac conduction system abnormalities in mice with targeted disruption of Six5 gene.
abstract: Myotonic dystrophy (DM) is an autosomal dominant multisystem disorder, caused by expansion of a CTG trinucleotide repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene (DMPK) on chromosome 19q13. Cardiac involvement in DM includes conduction abnormalities and functional deficits. Three hypotheses of molecular mechanisms for DM pathophysiology are; first, partial loss of myotonic dystrophy protein kinase (DMPK); second, decreased transcription of a neighboring homeodomain-encoding gene, Six5 (or DMAHP), and third, transdominant effects of the RNA and regulation of splicing associated with expression of expanded CUG repeats. However, the precise pathogenetic mechanism remains unresolved. We previously reported that dosage of Dm15, the mouse homologue of DMPK, strongly associates with the cardiac conduction abnormalities. For further distinction of the molecular mechanisms underlying the cardiac phenotype of DM, in the present study, we characterized the cardiac conduction findings of mice with targeted disruption of Six5 gene. Six5 heterozygous mice (adult and young) and their age matched wild type littermates were studied using in vivo electrophysiologic techniques, echocardiography, heart rate variability and exercise tolerance testing. No PR prolongation was detected, however, prolonged QRS duration and delayed infraHisian conduction were significant in adult Six5 heterozygous mice. By echocardiography, left ventricular (LV) end-diastolic dimension was enlarged in adult Six5 heterozygous mice, although neither fractioning shortening nor LV wall thickness showed significant differences. Six5 loss may partly contribute to conduction abnormalities in myotonic dystrophy, particularly infraHisian conduction delay, one of the initial phenotypes of adult-onset cardiac conduction abnormalities in DM patients.
authors.affiliation: Department of Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Colin T
authors.initials: CT
authors.lastname: Maguire
authors.forename: Megan C
authors.initials: MC
authors.lastname: Sherwood
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Vargas
authors.forename: Partha S
authors.initials: PS
authors.lastname: Sarkar
authors.forename: Jennifer
authors.initials: J
authors.lastname: Han
authors.forename: Sita
authors.initials: S
authors.lastname: Reddy
authors.forename: Charles I
authors.initials: CI
authors.lastname: Berul
mesh_terms: D000818:Animals; D004452:Echocardiography; D004562:Electrocardiography; D004594:Electrophysiology; D017353:Gene Deletion; D006329:Heart Conduction System / Q000002:abnormalities* / Q000503:physiopathology; D006339:Heart Rate; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D008991:Monitoring, Physiologic / Q000379:methods; D009043:Motor Activity / Q000502:physiology; D010807:Physical Endurance; D013686:Telemetry
chemical_list: D018398:Homeodomain Proteins; C486344:Six5 protein, mouse