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Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy

Jens Mogensen, MD, PhD^*,*, Ross T. Murphy, MD^*, Tony Shaw, PhD^*, Ajay Bahl, MD^*, Charles Redwood, PhD, Hugh Watkins, MD, PhD, Margaret Burke, MD, Perry M. Elliott, MD^* and William J. McKenna, MD^*

^* Department of Cardiological Sciences, St. George's Hospital Medical School, London, United Kingdom
Harefield Hospital, Middlesex, United Kingdom
John Radcliffe Hospital, Oxford, United Kingdom

View larger version (18K): [in a new window]   Figure 1 Pedigree drawings of dilated cardiomyopathy (DCM) families affected by cardiac troponin C and T mutations. All individuals had normal left ventricular wall thickness by echocardiography, and no patients had atrioventricluar block or impaired skeletal muscle function. Squares = male family members; circles = female family members; symbols with slash = deceased individuals; open symbols = unaffected individuals; solid symbols = individuals affected by DCM; half-solid symbols = individual with left ventricle enlargement; checkered symbols = individuals who died suddenly; question marks = unknown clinical status; plus signs = presence of mutation; minus signs = absence of mutation.

View larger version (12K): [in a new window]   Figure 2 Schematic representation of the human cardiac troponin T gene showing interaction sites with other thin filament sarcomeric contractile proteins (18–22). The stars indicate mutations identified in patients with dilated cardiomyopathy (DCM), R131W in family B, R205L in family C, K210 in family D, and D270N in family E.

View larger version (25K): [in a new window]   Figure 3 Effect of troponin C (cTnCG159D) and troponin T (cTnTR131W, cTnTR205L, cTnTK210, cTnTD270N) mutations on inter-troponin interactions assessed by a mammalian two-hybrid assay. All mutations impaired cTnT-cTnC and cTnT-cTnI interaction significantly (p < 0.001) compared with wild-type protein interaction (cTnTwt, cTnCwt, cTnIwt). A recognized troponin T polymorphism (cTnTK253R) did not change inter-troponin interaction significantly compared with wild-type troponin interaction. All experiments were repeated 10 times. Vertical bars = standard deviation.