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Genetic Disorders of the Cardiovascular System Brenda Gerull (Helmholtz Fellow) Chronic heart failure and sudden cardiac death are the clinical endpoints of many cardiovascular diseases including coronary artery disease, systemic hypertension and the various forms of ´primary´ heart muscle disorders, i.e. cardiomyopathies. Molecular genetics offers a unique opportunity to study the fundamental mechanisms leading to heart failure and sudden death in the cardiomyopathies (CMPs). Genetic defects are common in all forms of primary CMPs. The aim of our work is to unravel the genetic basis of these disorders and to dissect disease pathways. Mutations in the giant filament titin cause DCM Michael Gramlich Familial Dilated Cardiomyopathy (DCM) is a genetic disorder of the myocardium with progressive dilatation of the left or both ventricles. In large DCM families, positional candidate efforts have previously led to the identification of mutations in titin (TTN) associated with non-syndromic DCM. TTN encodes for the largest known protein found so far in nature. It serves as a scaffold in the sarcomere, plays a role in myofilament turnover and, in myocyte signal transduction. In one of the families we have found a segregating 2bp insertion mutation (c.43628insAT) causes a frame shift, thereby truncating A-band titin. The 2bp insertion mutation in human exon 326 has been cloned and introduced into the mouse genome. Homozygous mice die in utero before ED9.5 and heterozygous mice recapitulate the human DCM phenotype. In two other large DCM families we have found mutations in TTN: a missense mutation, W930R, and a frameshift mutation, K20963fsX20972, which results in a premature stop codon. Due to its enormous size and multiple functions titin is a prominent target for mutations and may account for a significant proportion of the genetic etiology of familial DCM. The role of plakophilin 2 and other desmosomal proteins in the pathogenesis of ARVC Arnd Heuser, Florian Kirchner Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disorder characterized by progressive loss of cardiomyocytes and fibrofatty replacement. ARVC often presents with ventricular arrhythmias that are a major cause of sudden death in the young, especially during physical activity. We have described mutations in plakophilin 2 (PKP2) and desmocollin 2 (DSC2) as a cause of autosomal dominant ARVC for the first time. PKP2 mutations account for a significant proportion of ARVC cases (10-45%). PKP2 and DSC2 are components of the desmosomal intercellular junction complex (see Figure) known to be essential for maintaining tissue integrity and increasingly implicated in cell signalling. While the involvement of multiple desmosomal protein genes has led to speculation regarding the sensitivity of myocardium to mechanical disruption, the pathogenic mechanisms leading to ARVC in humans are largely unknown. We are studying the molecular mechanisms (in vivo and in vitro) of ARVC in detail using cell culture experiments and different mouse models (conditional knockout or induced expression models of wildtype and mutant desmosomal proteins). In addition we are screening genes encoding other junctional components for the presence of mutations in a large cohort of ARVC patients. 30 Cardiovascular and Metabolic Disease Research
Structure of the Group Group Leader Dr. Brenda Gerull Scientists Dr. Michael Gramlich Arnd Heuser Graduate Students Florian Kirchner* Technical Assistants Ilona Trippmacher* Iska Liebner* * part of the period reported Cardiac myocytes Adherens junction Desmosome Gap junction Right ventricle ARVC predominantly affects the right ventricle of the heart and is considered to be a disease of the cellular junction complex (modified from J Clin Invest. 2006 Jul;116(7):1825-8). Selected Publications Heuser A, Plovie ER, Ellinor PT, Grossmann, KS, Shin JT, Wichter T, Basson CT, Lerman BB, Sasse-Klaassen S, Thierfelder L, MacRae CA, Gerull B. (2006). Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy (ARVC). Am J Hum Genet. Dec;79 (6):1081-8. Gerull B, Atherton J, Geupel A, Sasse-Klaassen S, Heuser A, Frenneaux M, McNabb M, Granzier H, Labeit S, Thierfelder L. (2006). Identification of a novel frameshift mutation in the giant TTN in a large Australian family with dilated cardiomyopathy. J Mol Med. Jun;84(6):478-83. Ellinor PT, Sasse-Klaassen S, Probst S, Gerull B, Shin JT, Toeppel A, Heuser A, Michely B, Yoerger DM, Song BS, Krings G, Coplin B, Dec GW, Hennies HC, Thierfelder L, MacRae CA. (2006). A novel locus for early-onset dilated cardiomyopathy, diffuse myocardial fibrosis and sudden death on chromosome 10q25-26. J Am Coll Cardiol. Jul 4;48(1):106-11. Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, Macrae CA, Peters S, Grossmann KS, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L.(2004). Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. [Corrigendum in: Nat Genet. 2005 Jan;37(1):106]. Nat. Genet. 36, 1162- 1164. Cardiovascular and Metabolic Disease Research 31
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