Restrictive cardiomyopathy (RCM) is an uncommon heart muscle disorder characterized by impaired filling of the ventricles with reduced volume in the presence of normal or near normal wall thickness and systolic function. The disease may be associated with systemic disease but is most often idiopathic. We recognized a large family in which individuals were affected by either idiopathic RCM or hypertrophic cardiomyopathy (HCM). Linkage analysis to selected sarcomeric contractile protein genes identified cardiac troponin I (TNNI3) as the likely disease gene. Subsequent mutation analysis revealed a novel missense mutation, which cosegregated with the disease in the family (lod score: 4.8). To determine if idiopathic RCM is part of the clinical expression of TNNI3 mutations, genetic investigations of the gene were performed in an additional nine unrelated RCM patients with restrictive filling patterns, bi-atrial dilatation, normal systolic function, and normal wall thickness. TNNI3 mutations were identified in six of these nine RCM patients. Two of the mutations identified in young individuals were de novo mutations. All mutations appeared in conserved and functionally important domains of the gene.
Jens Mogensen, Toru Kubo, Mauricio Duque, William Uribe, Anthony Shaw, Ross Murphy, Juan R. Gimeno, Perry Elliott, William J. McKenna
Cholesterol-loaded macrophage foam cells are a central component of atherosclerotic lesions. ABCA1, the defective molecule in Tangier disease, mediates the efflux of phospholipids and cholesterol from cells to apoA-I, reversing foam cell formation. In ABCA1, we identified a sequence rich in proline, glutamic acid, serine, and threonine (PEST sequence) that enhances the degradation of ABCA1 by calpain protease and thereby controls the cell surface concentration and cholesterol efflux activity of ABCA1. In an apparent positive feedback loop, apoA-I binds ABCA1, promotes lipid efflux, inhibits calpain degradation, and leads to increased levels of ABCA1. ApoA-I infusion also increases ABCA1 in vivo. These studies reveal a novel mode of regulation of ABCA1 by PEST sequence–mediated calpain proteolysis that appears to be reversed by apolipoprotein-mediated phospholipid efflux. Inhibition of ABCA1 degradation by calpain could represent a novel therapeutic approach to increasing macrophage cholesterol efflux and decreasing atherosclerosis.
Nan Wang, Wengen Chen, Patrick Linsel-Nitschke, Laurent O. Martinez, Birgit Agerholm-Larsen, David L. Silver, Alan R. Tall
Emily R. Eden, Dilipkumar D. Patel, Xi-Ming Sun, Jemima J. Burden, Michael Themis, Matthew Edwards, Philip Lee, Clare Neuwirth, Rossitza P. Naoumova, Anne K. Soutar
Colleen E. Clancy, Michihiro Tateyama, Robert S. Kass
Gregory A. Graf, Wei-Ping Li, Robert D. Gerard, Ingrid Gelissen, Ann White, Jonathan C. Cohen, Helen H. Hobbs
Liqing Yu, Jia Li-Hawkins, Robert E. Hammer, Knut E. Berge, Jay D. Horton, Jonathan C. Cohen, Helen H. Hobbs
Roshni R. Singaraja, Catherine Fievet, Graciela Castro, Erick R. James, Nathalie Hennuyer, Susanne M. Clee, Nagat Bissada, Jonathan C. Choy, Jean-Charles Fruchart, Bruce M. McManus, Bart Staels, Michael R. Hayden