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ObjectivesWe sought to explore the relationship between a Tcap gene (TCAP)abnormality and cardiomyopathy.BackgroundHypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cause severe heart failure and sudden death. Recent genetic investigations have revealed that mutations of genes encoding Z-disc components, including titin and muscle LIM protein (MLP), are the primary cause of both HCM and DCM. The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor. Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc.MethodsThe TCAPwas analyzed in 346 patients with HCM (236 familial and 110 sporadic cases) and 136 patients with DCM (34 familial and 102 sporadic cases). Two different in vitro qualitative assays—yeast two-hybrid and glutathion S-transferase pull-down competition—were performed in order to investigate functional changes in Tcap's interaction with MLP, titin, and calsarcin-1 caused by the identified mutations and a reported DCM-associated mutation, R87Q.ResultsTwo TCAPmutations, T137I and R153H, were found in patients with HCM, and another TCAPmutation, E132Q, was identified in a patient with DCM. It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1.ConclusionsThese observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components.

Dilated cardiomyopathy (DCM), a primary disorder of the cardiac muscle characterized by ventricular chamber dilation and diminished cardiac contractility (1), is the most common cause of chronic heart failure (CHF) in the young and the most common indication for cardiac transplantation (2). The underlying etiologies are varied and include genetic, viral (myocarditis), toxins like alcohol, mitochondrial, and metabolic disorders (3–6). Familial inheritance is seen in ≈30% to 40% of DCM patients (5). Autosomal dominant mode of inheritance is the most common (≈90%), followed by X-linked (5% to 10%), autosomal recessive, and mitochondrial inheritance patterns (

Category: Electrophysiology--BasicPresentation Number: 1078-125Authors: Yutao Xi, Tomohiko AI, Zhaohui Li, Geru Wu, Enkhsaikhan Purevjav, Shahrzad Abbasi, Jie Cheng, Matteo Vatta, Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke’s Episcopal Hospital, Hoston, TX, Pediatric Cardiology, Texas Children’s Hospital/Baylor College of Medicine, Houston, TX Background: Dilated cardiomyopathy (DCM) is often associated with conduction system diseases. However, the underlying molecular mechanisms remain unclear. We have previously identified the D117N mutation in the Z-band Alternatively Spliced PDZ motif (ZASP1), in a DCM patient with conduction disturbances, while the ZASP1-K136M was found in a DCM subject with no conduction defects. This study sought to elucidate the role of ZASP1-D117N in regulating the cardiac sodium channel (hNav1.5), which is critically involved in conduction system diseases. Methods: Patch-clamp techniques were used to measure INa in either HEK293 cells stably expressing hNav1.5 or neonatal rat cardiomyocytes (NRCM), both transiently transfected with WT or mutant ZASP1. Pull-down assay and immunohistochemistry (IHC) analysis were employed to study the interaction and localization between hNav1.5, WT and mutant ZASP and other cytoskeletal proteins.Results: Macroscopic INa were significantly decreased in cells expressing D117N compared to WT and K136M (WT, -252.0 ± 24.5 pA/pF, n = 20; K136M, -259.7 ± 37.1 pA/pF, n = 17; D117N, -182.2 ± 18.5 pA/pF, p