title: HCM-linked ∆160E cardiac troponin T mutation causes unique progressive structural and molecular ventricular remodeling in transgenic mice.
abstract: Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle, and one of the most common causes of sudden cardiac death (SCD) in young people. Many mutations in cardiac troponin T (cTnT) lead to a complex form of HCM with varying degrees of ventricular hypertrophy and ~65% of all cTnT mutations occur within or flanking the elongated N-terminal TNT1 domain. Biophysical studies have predicted that distal TNT1 mutations, including Δ160E, cause disease by a novel, yet unknown mechanism as compared to N-terminal mutations. To begin to address the specific effects of this commonly observed cTnT mutation we generated two independent transgenic mouse lines carrying variant doses of the mutant transgene. Hearts from the 30% and 70% cTnT Δ160E lines demonstrated a highly unique, dose-dependent disruption in cellular and sarcomeric architecture and a highly progressive pattern of ventricular remodeling. While adult ventricular myocytes isolated from Δ160E transgenic mice exhibited dosage-independent mechanical impairments, decreased sarcoplasmic reticulum calcium load and SERCA2a calcium uptake activity, the observed decreases in calcium transients were dosage-dependent. The latter findings were concordant with measures of calcium regulatory protein abundance and phosphorylation state. Finally, studies of whole heart physiology in the isovolumic mode demonstrated dose-dependent differences in the degree of cardiac dysfunction. We conclude that the observed clinical severity of the cTnT Δ160E mutation is caused by a combination of direct sarcomeric disruption coupled to a profound dysregulation of Ca(2+) homeostasis at the cellular level that results in a unique and highly progressive pattern of ventricular remodeling.
authors: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Avenue, Ullmann, Room 316, Bronx, NY 10461, USA.
authors: Rachel K
authors: RK
authors: Moore
authors: Lauren Tal
authors: LT
authors: Grinspan
authors: Jesus
authors: J
authors: Jimenez
authors: Pia J
authors: PJ
authors: Guinto
authors: Briar
authors: B
authors: Ertz-Berger
authors: Jil C
authors: JC
authors: Tardiff
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000473:pathology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012518:Sarcomeres / Q000235:genetics / Q000473:pathology; D020107:Troponin T / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D020107:Troponin T